A Narrowing-based Instantiation Rule for Rewriting-based Fold/Unfold Transformations

In this paper we show how to transfer some developments done in the field of functionallogic programming (FLP) to a pure functional setting (FP). More exactly, we propose a complete fold/unfold based transformation system for optimizing lazy functional programs. Our main contribution is the definition of a safe instantiation rule which is used to enable effective unfolding steps based on rewriting. Since instantiation has been traditionally considered problematic in FP, we take advantage of previous experiences in the more general setting of FLP where instantiation is naturally embedded into an unfolding rule based on narrowing. Inspired by the so called needed narrowing strategy, our instantiation rule inherits the best properties of this refinement of narrowing. Our proposal optimizes previous approaches (that require more transformation effort) defined in the specialized literature of pure FP by anticipating bindings on unifiers used to instantiate a given program rule and by generating redexes at different positions on instantiated rules in order to enable subsequent unfolding steps. As a consequence, our correct/complete technique avoids redundant rules and preserves the natural structure of programs.     

Stochastic stabilization of differential systems with general decay rate

Some sufficient conditions concerning stability of solutions of stochastic differential evolution equations with general decay rate are first proved. Then, these results are interpreted as suitable stabilization ones for deterministic and stochastic systems. Also, they permit us to construct appropriate linear stabilizers in some particular situations.     

Simulation based on learning methods

The use of simulation technology as a tool for planning and control is of increasing significance in most fields of production. The main part of the expenditure concerning simulation analyses is the modelling of the considered production. Despite the use of modern building-block-oriented modelling technology, this modelling can often not be done by the user, but only by external experts. Against this backdrop, an adaptive simulation system is being developed by the Institute for Industrial Manufacturing and Management (IFF) at the University of Stuttgart. It independently adapts to real production processes, i.e. it learns about the interdependencies of production processes, and, in this way, supports the user in constructing and maintaining the model. In terms of information technology, the research in the field of artificial intelligence, especially in the subdomain of machine learning, is the basis for the realization of such adaptive systems.     

Characterization of cerium and copper species in Cu—Ce—Al oxide systems by temperature programmed reduction and electron paramagnetic resonance

The reducibility of Ce—Al—O and Cu—Ce—Al—O solids is studied by H₂-TPR and EPR in order to identify the different ceria and copper oxide species. The study of Ce—Al—O oxides shows that dispersion of ceria on alumina improves reducibility of ceria bulk and stabilizes surface ceria. Concerning quantitative results, ceria reduction extent is more important for Ce—Al—O oxides than for pure ceria. This result can be related to the dispersion of ceria on alumina which decreases ceria crystallites size and enhances the ceria bulk reduction. For ternary oxides, copper oxide and ceria interact strongly. Introduction of copper facilitated ceria reduction, and quantitatively, the presence of copper favors the total reduction of ceria contrary to Ce—Al—O oxides. When ceria loading is low, two copper species are identified, and are attributed to small clusters and highly dispersed copper oxides. During the reduction of copper species, a partial reduction of ceria is observed. Increasing of copper loading leads to the formation of CuO aggregates.     

Aluminium and silicon base coatings for high temperature alloys—Process development and comparison of properties

The paper is concerned with systematic studies on the formation of overlay coatings on nickel and iron base superalloys to improve their resistance against high temperature oxidation and hot corrosion. In contrast to the simpler case of aluminizing nickel base alloys, the problems arising in aluminizing iron base superalloys and in siliconizing nickel base alloys have not yet been solved.A new and economical coating procedure is presented, which involves a reaction sintering process of unalloyed powder mixtures to obtain overlay coatings. The influence of the compositions of the layer and the substrate on the chemical compatibility of the whole layer composite is described in detail. It is shown that overlay coatings containing high concentrations of silicon can only be applied on nickel base superalloys if elements that are able spontaneously to form reaction barriers are present within the substrate alloy (e.g. aluminium) or in the as-preformed interlayer. Refractory metals have proved to be the most advantageous.To obtain a ductile coating, silicon-rich donor phases in the form of isolated precipitates were incorporated into a matrix containing low concentrations of silicon. These coating systems can also be applied to improve the aluminization of iron base alloys. The high temperature oxidation and corrosion behaviours of the coated samples were tested in burner gas or air at 1000°C and in molten salts at 900°C.     

Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06

The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I₂ receptors (I₂-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I₂-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age-related cognitive decline and the other for Alzheimer’s disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson’s disease (PD). B06 rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine (6-OHDA) and showed a crucial anti-inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I₂-IR as a fresh approach for the therapy of ND.     

Role of miRNAs in Human T Cell Leukemia Virus Type 1 Induced T Cell Leukemia: A Literature Review and Bioinformatics Approach

Human T cell leukemia virus type 1 (HTLV-1) was identified as the first pathogenic human retrovirus and is estimated to infect 5 to 10 million individuals worldwide. Unlike other retroviruses, there is no effective therapy to prevent the onset of the most alarming diseases caused by HTLV-1, and the more severe cases manifest as the malignant phenotype of adult T cell leukemia (ATL). MicroRNA (miRNA) dysfunction is a common feature of leukemogenesis, and it is no different in ATL cases. Therefore, we sought to analyze studies that reported deregulated miRNA expression in HTLV-1 infected cells and patients’ samples to understand how this deregulation could induce malignancy. Through in silico analysis, we identified 12 miRNAs that stood out in the prediction of targets, and we performed functional annotation of the genes linked to these 12 miRNAs that appeared to have a major biological interaction. A total of 90 genes were enriched in 14 KEGG pathways with significant values, including TP53, WNT, MAPK, TGF-β, and Ras signaling pathways. These miRNAs and gene interactions are discussed in further detail for elucidation of how they may act as probable drivers for ATL onset, and while our data provide solid starting points for comprehension of miRNAs’ roles in HTLV-1 infection, continuous effort in oncologic research is still needed to improve our understanding of HTLV-1 induced leukemia.     

Multiplexed-Based Assessment of DNA Damage Response to Chemotherapies Using Cell Imaging Cytometry

The current methods for measuring the DNA damage response (DDR) are relatively labor-intensive and usually based on Western blotting, flow cytometry, and/or confocal immunofluorescence analyses. They require many cells and are often limited to the assessment of a single or few proteins. Here, we used the Celigo^® image cytometer to evaluate the cell response to DNA-damaging agents based on a panel of biomarkers associated with the main DDR signaling pathways. We investigated the cytostatic or/and the cytotoxic effects of these drugs using simultaneous propidium iodide and calcein-AM staining. We also describe new dedicated multiplexed protocols to investigate the qualitative (phosphorylation) or the quantitative changes of eleven DDR markers (H2AX, DNA-PKcs, ATR, ATM, CHK1, CHK2, 53BP1, NBS1, RAD51, P53, P21). The results of our study clearly show the advantage of using this methodology because the multiplexed-based evaluation of these markers can be performed in a single experiment using the standard 384-well plate format. The analyses of multiple DDR markers together with the cell cycle status provide valuable insights into the mechanism of action of investigational drugs that induce DNA damage in a time- and cost-effective manner due to the low amounts of antibodies and reagents required.     

Establishing In-House Cutoffs of CSF Alzheimer’s Disease Biomarkers for the AT(N) Stratification of the Alzheimer Center Barcelona Cohort

Background: Clinical diagnosis of Alzheimer’s disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivity/negativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases. Methods: We quantified CSF Aβ1-42, Aβ1-40, t-Tau, and p181Tau with standard INNOTEST^® ELISA and Lumipulse G^® chemiluminescence enzyme immunoassay (CLEIA) performed on the automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with probable Alzheimer’s disease (AD, n = 37) and subjective cognitive decline subjects (SCD, n = 45), cognitively stable for 3 years and with no evidence of brain amyloidosis in 18F-Florbetaben-labeled positron emission tomography (FBB-PET). To compare both methods, a subset of samples for Aβ1-42 (n = 519), t-Tau (n = 399), p181Tau (n = 77), and Aβ1-40 (n = 44) was analyzed. Kappa agreement of single biomarkers and Aβ1-42/Aβ1-40 was evaluated in an independent group of mild cognitive impairment (MCI) and dementia patients (n = 68). Next, established cutoffs were applied to a large real-world cohort of MCI subjects with follow-up data available (n = 647). Results: Cutoff values of Aβ1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aβ1-40 and 0.96 for p181TAU. Passing–Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aβ1-40. Bland–Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the Aβ1-42/Aβ1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan–Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates (p = 9.815⁻²⁷). Multivariate Cox proportional hazard models corroborated these findings, demonstrating that the proposed AT(N) classifier has prognostic value. AT(N) categories are only modestly influenced by other known factors associated with disease progression. Conclusions: We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects.     

Arabinoxylan and Pectin Metabolism in Crohn’s Disease Microbiota: An In Silico Study

Inflammatory bowel disease is a chronic disorder including ulcerative colitis and Crohn’s disease (CD). Gut dysbiosis is often associated with CD, and metagenomics allows a better understanding of the microbial communities involved. The objective of this study was to reconstruct in silico carbohydrate metabolic capabilities from metagenome-assembled genomes (MAGs) obtained from healthy and CD individuals. This computational method was developed as a mean to aid rationally designed prebiotic interventions to rebalance CD dysbiosis, with a focus on metabolism of emergent prebiotics derived from arabinoxylan and pectin. Up to 1196 and 1577 MAGs were recovered from CD and healthy people, respectively. MAGs of Akkermansia muciniphila, Barnesiella viscericola DSM 18177 and Paraprevotella xylaniphila YIT 11841 showed a wide range of unique and specific enzymes acting on arabinoxylan and pectin. These glycosidases were also found in MAGs recovered from CD patients. Interestingly, these arabinoxylan and pectin degraders are predicted to exhibit metabolic interactions with other gut microbes reduced in CD. Thus, administration of arabinoxylan and pectin may ameliorate dysbiosis in CD by promoting species with key metabolic functions, capable of cross-feeding other beneficial species. These computational methods may be of special interest for the rational design of prebiotic ingredients targeting at CD.