Optimal control approach for discontinuous dynamical systems

In this work, we consider a wide class of discontinuous dynamical systems, discontinuity of which is based on the sign (for short sgn) function. We propose a smooth optimal control problem to solve the main discontinuous system. By solving some numerical examples in mechanical engineering, we show the efficiency of our approach with respect to 2 smoothing methods for discontinuous systems.     

Scoring of nonmetric cranial traits: a population study

The aims of the present study were: (1) to supply further knowledge about variations in nonmetric cranial traits in relation to sex, age and laterality and (2) to evaluate biological distance between samples from a recent population. The incidence of 18 nonmetric variants of the cranium were determined in 3 adult samples of 394 skulls of known sex from North Sardinia (Sassari, Alghero and Ozieri); for the Sassari sample (n = 200) age at death was also known. Some significant sex differences were observed. Age did not appear to influence the frequency of the discontinuous traits but did for legibility. Side differences may provide important information about environmental influences. The interpopulation analysis indicates a stronger relationship between samples that are geographically closer (Sassari and Alghero), in accordance with other studies, strengthening the hypothesis of the validity of the use of nonmetric traits in the study of the peopling of a territory.     

Prognostic significance of laminin in adenocarcinoma of the lung

The distribution of laminin in tumor-associated basement membrane was immunohistochemically investigated in 115 cases of adenocarcinoma of the lung. The distribution of laminin was classified into continuous and discontinuous staining patterns. The incidence of the discontinuous pattern was less in early-stage disease than that in advanced stages (P less than 0.01). In patients with stage I, the incidence of discontinuous patterns was greater in short-term survivors than in long-term survivors (P less than 0.05). By contrast, in patients with stage III, the discontinuous pattern of laminin was frequently seen in both long-term survivors and short-term survivors, with no difference between the two groups. These data suggest that the discontinuous pattern of laminin in tumor-associated basement membrane reflects the spread and dissemination of tumor, hence a close relationship to the prognosis.     

Effect of Boron Doping on Cellular Discontinuous Precipitation for Age-Hardenable Cu–Ti Alloys

The effects of boron doping on the microstructural evolution and mechanical and electrical properties of age-hardenable Cu–4Ti (at.%) alloys are investigated. In the quenched Cu–4Ti–0.03B (at.%) alloy, elemental B (boron) is preferentially segregated at the grain boundaries of the supersaturated solid-solution phase. The aging behavior of the B-doped alloy is mostly similar to that of conventional age-hardenable Cu–Ti alloys. In the early stage of aging at 450 °C, metastable β′-Cu₄Ti with fine needle-shaped precipitates continuously form in the matrix phase. Cellular discontinuous precipitates composed of the stable β-Cu₄Ti and solid-solution laminates are then formed and grown at the grain boundaries. However, the volume fraction of the discontinuous precipitates is lower in the Cu–4Ti–0.03B alloy than the Cu–4Ti alloy, particularly in the over-aging period of 72–120 h. The suppression of the formation of discontinuous precipitates eventually results in improvement of the hardness and tensile strength. It should be noted that minor B doping of Cu–Ti alloys also effectively enhances the elongation to fracture, which should be attributed to segregation of B at the grain boundaries.     

Yield-Point Phenomenon and Plastic Bands in Ferrite–Pearlite Steels

Lüders deformation is one type of discontinuous yielding in ferrite–pearlite steel. The yield-point phenomenon and localized plastic bands are two features of the Lüders phenomenon. It is believed that the yield-point phenomenon is related to the formation of plastic bands, but the correlation between them is unclear. In this study, this correlation was investigated by examining the global and local deformation behaviors in the tension processes of four ferrite–pearlite steels (carbon content, 0.05–0.3%; pearlite fraction, 1.2–32%) via an extensometer and digital image correlation (DIC) technique. The main obtained results are as follows: (1) the degree of yield drop decreased with an increase in the pearlite fraction (the magnitude of the yield stress drop was 8.6–0 MPa), and (2) a plastic band was formed at a certain stress level smaller than the upper yield stress; when the stress level was larger than 92% of the upper yield stress, the upper yield point disappeared.     

Discontinuous epitopes on the C2 domain of coagulation Factor VIII mapped by computer-designed synthetic peptides

The occurrence of alloantibodies against Factor VIII (FVIII) is the main iatrogenic complication in haemophilia A (HA). Anti-FVIII autoantibodies may also spontaneously appear in non-HA patients, leading to acquired haemophilia A. In both contexts, the antibody response against FVIII is complex and difficult to analyse due to the lack of suitable tools. Our purpose was to comprehensively map, at the amino acid level, discontinuous epitopes of the C2 domain of FVIII targeted by patients' antibodies. We synthesized 33 synthetic peptides, which were predicted by the bioinformatic algorithm PEPOP to mimic C2 domain discontinuous epitopes. Using an inhibition assay based on the x-MAP technology, we evaluated their ability to block the binding to the C2 domain of anti-C2 domain antibodies from pooled plasma samples. Nine peptides were thus selected and tested again in individual plasma samples. Our results support the view that C2 domain epitopes are organized as an epitopic mosaic distributed around the molecule, showed that each patient displayed a specific anti-C2 epitopic profile, and confirmed the complexity and variability of the immune response against the C2 domain of FVIII. This ability to finely map epitopes could be further used to follow the antibody specificity modifications over time.     

Why Does the Molecular Structure of Broadly Neutralizing Monoclonal Antibodies Isolated from Individuals Infected with HIV-1 not Inform the Rational Design of an HIV-1 Vaccine?

It is commonly assumed that neutralizing Mabs that bind to the HIV-1 Env glycoprotein are more specific reagents than anti-HIV-1 polyclonal antisera and that knowledge of the structure of these Mabs facilitates the rational design of effective HIV-1 vaccine immunogens. However, after more than ten years of unsuccessful experimentation using the structure-based reverse vaccinology approach, it is now evident that it is not possible to infer from the structure of neutralizing Mabs which HIV immunogens induced their formation nor which vaccine immunogens will elicit similar Abs in an immunized host. The use of Mabs for developing an HIV-1 vaccine was counterproductive because it overlooked the fact that the apparent specificity of a Mab very much depends on the selection procedure used to obtain it and also did not take into account that an antibody is never monospecific for a single epitope but is always polyspecific for many epitopes. When the rationale of the proponents of the unsuccessful rational design strategy is analyzed, it appears that investigators who claim they are designing a vaccine immunogen are only improving the binding reactivity of a single epitope-paratope pair and are not actually designing an immunogen able to generate protective antibodies. The task of a designer consists in imagining what type of immunogen is likely to elicit a protective immune response but in the absence of knowledge regarding which features of the immune system are responsible for producing a functional neutralizing activity in antibodies, it is not feasible to intentionally optimize a potential immunogen candidate in order to obtain the desired outcome. The only available option is actually to test possible solutions by trial-and-error experiments until the preset goal is perhaps attained. Rational design and empirical approaches in HIV vaccine research should thus not be opposed as alternative options since empirical testing is an integral part of a so-called design strategy.     

In silico Design of Discontinuous Peptides Representative of B and T-cell Epitopes from HER2-ECD as Potential Novel Cancer Peptide Vaccines

At present, the most common cause of cancer-related death in women is breast cancer. In a large proportionof breast cancers, there is the overexpression of human epidermal growth factor receptor 2 (HER2). This receptoris a 185 KDa growth factor glycoprotein, also known as the first tumor-associated antigen for different typesof breast cancers. Moreover, HER2 is an appropriate cell-surface specific antigen for passive immunotherapy,which relies on the repeated application of monoclonal antibodies that are transferred to the patient. However,vaccination is preferable because it would stimulate a patient’s own immune system to actively respond to adisease. In the current study, several bioinformatics tools were used for designing synthetic peptide vaccines.PEPOP was used to predict peptides from HER2 ECD subdomain III in the form of discontinuous-continuousB-cell epitopes. Then, T-cell epitope prediction web servers MHCPred, SYFPEITHI, HLA peptide motif search,Propred, and SVMHC were used to identify class-I and II MHC peptides. In this way, PEPOP selected 12discontinuous peptides from the 3D structure of the HER2 ECD subdomain III. Furthermore, T-cell epitopeprediction analyses identified four peptides containing the segments 77 (384-391) and 99 (495-503) for both Band T-cell epitopes. This work is the only study to our knowledge focusing on design of in silico potential novelcancer peptide vaccines of the HER2 ECD subdomain III that contain epitopes for both B and T-cells. Thesefindings based on bioinformatics analyses may be used in vaccine design and cancer therapy; saving time andminimizing the number of tests needed to select the best possible epitopes.     

Initiating Reentry:

Cellular Coupling as a Basis for Arrhythmias. Until recently only two types of media have been considered to provide the nonuniformities necessary to initiate cardiac reentry: (1) continuous isotropic media with intrinsic repolarization inhomogeneities; and (2) continuous isotropic media free of inhomogeneities in which repolarization nonuniformities are introduced transiently. The purpose of this article is to establish cellular coupling as a basis for arrhythmias by placing a new type of inhomogeneity, nonuniform anisotropy due to sparse side-to-side coupling between cells, in an overall perspective with the other nonuniformities that lead to reentry. Review of experimental and theoretical models of reentry leads to the following picture: with slowed conduction, reentrant circuits diminish in size and the nonuniformities necessary for reentry are provided by nonuniform anisotropy. Repolarization nonuniformities create functionally different pathways for reentrant circuits of relatively large size (> 30–50 mm²). Nonuniform anisotropic cellular coupling, which is associated with underlying microfibrosis, makes it possible for reentry to occur in small areas (< 10–15 mm²). A general property found in nonuniform anisotropic bundles is the presence of functionally different pathways in the absence of intrinsic repolarization inhomogeneities-one of fast longitudinal conduction with a longer refractory period, and another of “very slow” transverse conduction with a shorter refractory period. Since it is not known if nonuniform anisotropy exists in the AV node, the best known structure with small reentrant circuits, we performed microscopic extracellular measurements in the AV node of the rabbit. The transitional Zone of the AV node was found to have markedly nonuniform anisotropic conduction properties. The analysis provides the view that functionally different pathways of small reentrant circuits, including those of the AV node, need to be reevaluated in terms of the role of nonuniform anisotropic cellular coupling.