A Differential Evolution Framework with Ensemble of Parameters and Strategies and Pool of Local Search Algorithms

The file attached to this record is the author's final peer reviewed version. The publisher's final version can be found by following the DOI link.The ensemble structure is a computational intelligence supervised strategy consisting of a pool of multiple operators that compete among each other for being selected, and an adaptation mechanism that tends to reward the most successful operators. In this paper we extend the idea of the ensemble to multiple local search logics. In a memetic fashion, the search structure of an ensemble framework cooperatively/competitively optimizes the problem jointly with a pool of diverse local search algorithms. In this way, the algorithm progressively adapts to a given problem and selects those search logics that appear to be the most appropriate to quickly detect high quality solutions. The resulting algorithm, namely Ensemble of Parameters and Strategies Differential Evolution empowered by Local Search (EPSDE-LS), is evaluated on multiple testbeds and dimensionality values. Numerical results show that the proposed EPSDE-LS robustly displays a very good performance in comparison with some of the state-of-the-art algorithms

Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive transfer with tumor-infiltrating lymphocytes in melanoma

BACKGROUND: Neoantigen-driven recognition and T cell-mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with Tumor-Infiltrating Lymphocytes (TILs). Yet, how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined. METHODS: Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic mela-noma patients who received ACT. RESULTS: We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with in-creased survival, and that detection of engrafted CD8+ T cells in post-treatment (i.e. originating from the TIL infusion product) were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product. CONCLUSIONS: These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma, and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells. FUNDING: NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation

Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy

Mitophagy orchestrates the autophagic degradation of dysfunctional mitochondria preventing their pathological accumulation and contributing to cellular homeostasis. We previously identified a novel chemical tool (hereafter referred to as PMI), which drives mitochondria into autophagy without collapsing their membrane potential (ΔΨm). PMI is an inhibitor of the protein-protein interaction (PPI) between the transcription factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autophagy-associated proteins, including p62/SQSTM1. Here we show that PMI promotes mitochondrial respiration, leading to a superoxide-dependent activation of mitophagy. Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover, while covalent Keap1 modifiers, including sulforaphane (SFN) and dimethyl fumarate (DMF), are unable to induce a similar response. Additionally, we demonstrate that SFN reverses the effects of PMI in co-treated cells by reducing the accumulation of p62 in mitochondria and subsequently limiting their autophagic degradation. This study highlights the unique features of Keap1-Nrf2 PPI inhibitors as inducers of mitophagy and their potential as pharmacological agents for the treatment of pathological conditions characterized by impaired mitochondrial quality control

Time resolved spectroscopy of BD+46 442: gas streams and jet creation in a newly discovered evolved binary with a disk

Previous studies have shown that many post-AGB stars with dusty disks are associated with single-lined binary stars. To verify the binarity hypothesis on a larger sample, we started a high-resolution spectral monitoring of about 40 field giants, whose binarity was suspected based on either a light curve, an infrared excess, or a peculiar chemical composition. Here we report on the discovery of the periodic RV variations in BD+46 442, a high-latitude F giant with a disk. We interpret the variations due to the motion around a faint companion, and deduce the following orbital parameters: Porb = 140.77 d, e = 0.083, asini=0.31 AU. We find it to be a moderately metal-poor star ([M/H]=-0.7) without a strong depletion pattern in the photospheric abundances. Interestingly, many lines show periodic changes with the orbital phase: Halpha switches between a double-peak emission and a PCyg-like profiles, while strong metal lines appear split during the maximum redshift. Similar effects are likely visible in the spectra of other post-AGB binaries, but their regularity is not always realized due to sporadic observations. We propose that these features result from an ongoing mass transfer from the evolved giant to the companion. In particular, the blue-shifted absorption in Halpha, which occurs only at superior conjunction, may result from a jet originating in the accretion disk around the companion and seen in absorption towards the luminous primary.Comment: 16 pages, accepted in A&

Inducing persistent flow disturbances accelerates atherogenesis and promotes thin cap fibroatheroma development in D374Y-PCSK9 hypercholesterolemic minipigs

BACKGROUND: -Although disturbed flow is thought to play a central role in the development of advanced coronary atherosclerotic plaques, no causal relationship has been established. We evaluated whether inducing disturbed flow would cause the development of advanced coronary plaques, including thin cap fibroatheroma (TCFA). METHODS AND RESULTS: -D374Y-PCSK9 hypercholesterolemic minipigs (N=5) were instrumented with an intracoronary shear-modifying stent (SMS). Frequency-domain optical coherence tomography was obtained at baseline, immediately post-stent, 19, and 34 weeks and used to compute shear stress metrics of disturbed flow. At 34 weeks, plaque type was assessed within serially-collected histological sections and co-registered to the distribution of each shear metric. The SMS caused a flow-limiting stenosis and blood flow exiting the SMS caused regions of increased shear stress on the outer curvature and large regions of low and multidirectional shear stress on the inner curvature of the vessel. As a result, plaque burden was ~3-fold higher downstream of the SMS compared to both upstream of the SMS and in the control artery (p<0.001). Advanced plaques were also primarily observed downstream of the SMS, in locations initially exposed to both low (p<0.002) and multidirectional (p<0.002) shear stress. TCFA regions demonstrated significantly lower shear stress that persisted over the duration of the study compared to other plaque types (p<0.005). CONCLUSIONS: -These data support a causal role for lowered and multidirectional shear stress in the initiation of advanced coronary atherosclerotic plaques. Persistently lowered shear stress appears to be the principal flow disturbance needed for the formation of TCFA

An enhanced partial order curve comparison algorithm and its application to analyzing protein folding trajectories

<p>Abstract</p> <p>Background</p> <p>Understanding how proteins fold is essential to our quest in discovering how life works at the molecular level. Current computation power enables researchers to produce a huge amount of folding simulation data. Hence there is a pressing need to be able to interpret and identify novel folding features from them.</p> <p>Results</p> <p>In this paper, we model each folding trajectory as a multi-dimensional curve. We then develop an effective multiple curve comparison (MCC) algorithm, called the <it>enhanced partial order (EPO) </it>algorithm, to extract features from a set of diverse folding trajectories, including both successful and unsuccessful simulation runs. The EPO algorithm addresses several new challenges presented by comparing high dimensional curves coming from folding trajectories. A detailed case study on miniprotein Trp-cage <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> demonstrates that our algorithm can detect similarities at rather low level, and extract biologically meaningful folding events.</p> <p>Conclusion</p> <p>The EPO algorithm is general and applicable to a wide range of applications. We demonstrate its generality and effectiveness by applying it to aligning multiple protein structures with low similarities. For user's convenience, we provide a web server for the algorithm at <url>http://db.cse.ohio-state.edu/EPO</url>.</p

THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria

Phenotypic screens for bactericidal compounds against drug-resistant tuberculosis are beginning to yield novel inhibitors. However, reliable target identification remains challenging. Here, we show that tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide (THPP) selectively pulls down EchA6 in a stereospecific manner, instead of the previously assigned target Mycobacterium tuberculosis MmpL3. While homologous to mammalian enoyl-coenzyme A (CoA) hydratases, EchA6 is non-catalytic yet essential and binds long-chain acyl-CoAs. THPP inhibitors compete with CoA-binding, suppress mycolic acid synthesis, and are bactericidal in a mouse model of chronic tuberculosis infection. A point mutation, W133A, abrogated THPP-binding and increased both the in vitro minimum inhibitory concentration and the in vivo effective dose 99 in mice. Surprisingly, EchA6 interacts with selected enzymes of fatty acid synthase II (FAS-II) in bacterial two-hybrid assays, suggesting essentiality may be linked to feeding long-chain fatty acids to FAS-II. Finally, our data show that spontaneous resistance-conferring mutations can potentially obscure the actual target or alternative targets of small molecule inhibitors

Interrupting peptidoglycan deacetylation during Bdellovibrio predator-prey interaction prevents ultimate destruction of prey wall, liberating bacterial-ghosts

The peptidoglycan wall, located in the periplasm between the inner and outer membranes of the cell envelope in Gram-negative bacteria, maintains cell shape and endows osmotic robustness. Predatory Bdellovibrio bacteria invade the periplasm of other bacterial prey cells, usually crossing the peptidoglycan layer, forming transient structures called bdelloplasts within which the predators replicate. Prey peptidoglycan remains intact for several hours, but is modified and then degraded by predators escaping. Here we show predation is altered by deleting two Bdellovibrio N-acetylglucosamine (GlcNAc) deacetylases, one of which we show to have a unique two domain structure with a novel regulatory-”plug”. Deleting the deacetylases limits peptidoglycan degradation and rounded prey cell “ghosts” persist after mutant-predator exit. Mutant predators can replicate unusually in the periplasmic region between the peptidoglycan wall and the outer membrane rather than between wall and inner-membrane, yet still obtain nutrients from the prey cytoplasm. Deleting two further genes encoding DacB/PBP4 family proteins, known to decrosslink and round prey peptidoglycan, results in a quadruple mutant Bdellovibrio which leaves prey-shaped ghosts upon predation. The resultant bacterial ghosts contain cytoplasmic membrane within bacteria-shaped peptidoglycan surrounded by outer membrane material which could have promise as “bacterial skeletons” for housing artificial chromosomes

Can type of school be used as an alternative indicator of socioeconomic status in dental caries studies? A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Despite the importance of collecting individual data of socioeconomic status (SES) in epidemiological oral health surveys with children, this procedure relies on the parents as respondents. Therefore, type of school (public or private schools) could be used as an alternative indicator of SES, instead of collecting data individually. The aim of this study was to evaluate the use of the variable type of school as an indicator of socioeconomic status as a substitute of individual data in an epidemiological survey about dental caries in Brazilian preschool children.</p> <p>Methods</p> <p>This study followed a cross-sectional design, with a random sample of 411 preschool children aged 1 to 5 years, representative of Catalão, Brazil. A calibrated examiner evaluated the prevalence of dental caries and parents or guardians provided information about several individual socioeconomic indicators by means of a semi-structured questionnaire. A multilevel approach was used to investigate the association among individual socioeconomic variables, as well as the type of school, and the outcome.</p> <p>Results</p> <p>When all significant variables in the univariate analysis were used in the multiple model, only mother's schooling and household income (individual socioeconomic variables) presented significant associations with presence of dental caries, and the type of school was not significantly associated. However, when the type of school was used alone, children of public school presented significantly higher prevalence of dental caries than those enrolled in private schools.</p> <p>Conclusions</p> <p>The type of school used as an alternative indicator for socioeconomic status is a feasible predictor for caries experience in epidemiological dental caries studies involving preschool children in Brazilian context.</p