Evolution of biomarker research in autoimmunity conditions for health professionals and clinical practice.

Medical abzymology has made a great contribution to the development of general autoimmunity theory: it has put the autoantibodies (Ab) as the key brick of the theory to the level of physiological functionality by providing such Ab with the ability to catalyze and mediate direct and independent cytotoxic effect on cellular and molecular targets. Natural catalytic autoantibodies (abzymes) while being a pool of canonical Abs and possessing catalytic activity belong to the new group of physiologically active substances whose features and properties are evolutionary consolidated in one functionally active biomolecule. Therefore, further studies on Ab-mediated autoAg degradation and other targeted Ab-mediated proteolysis may provide biomarkers of newer generations and thus a supplementary tool for assessing the disease progression and predicting disability of the patients and persons at risks. This chapter is a summary of current knowledge and prognostic perspectives toward catalytic Abs in autoimmunity and thus some autoimmune clinical cases, their role in pathogenesis, and the exploitation of both whole molecules and their constituent parts in developing highly effective targeted drugs of the future to come, and thus the therapeutic protocols being individualized.

Frequency comb generation in SNAP fiber resonator based on axial-azimuthal mode interactions.

We study nonlinear mode interaction in the cylindrical microresonator with nanoscale radius variation. We obtain a model which describes the interplay between azimuthal modes and investigate the nonlinear dynamics of axial-azimuthal modes. We also define regimes of generation depending on the pump parameters. Using a properly designed radius longitudinal profile, we obtain broadband generation of stable low-repetition-rate frequency combs based on axial-azimuthal modes.

PEO Coatings Modified with Halloysite Nanotubes: Composition, Properties, and Release Performance.

In this work, the properties of the coatings formed on the Mg-Mn-Ce alloy by plasma electrolytic oxidation (PEO) in electrolytes containing halloysite nanotubes (HNTs) were investigated. The incorporation of halloysite nanotubes into the PEO coatings improved their mechanical characteristics, increased thickness, and corrosion resistance. The studied layers reduced corrosion current density by more than two times in comparison with the base PEO layer without HNTs (from 1.1 × 10-7 A/cm2 to 4.9 × 10-8 A/cm2). The presence of halloysite nanotubes and products of their dihydroxylation that were formed under the PEO conditions had a positive impact on the microhardness of the obtained layers (this parameter increased from 4.5 ± 0.4 GPa to 7.3 ± 0.5 GPa). In comparison with the base PEO layer, coatings containing halloysite nanotubes exhibited sustained release and higher adsorption capacity regarding caffeine.

Reflection of whispering gallery modes propagating on a surface of an optical fiber from its cleave.

We experimentally and numerically study the dynamics of whispering gallery modes slowly propagating within the cladding of an optical fiber near its end facet. We demonstrated that modes reflect from the fiber cleave. The reflection coefficient appears to reach 70% for the sample under study. Use of a facet provides a simple method to confine the axial propagation of the modes.

Nonlinear transition between PT-symmetric and PT-broken modes in coupled fiber lasers.

We present a systematic analysis of the stationary regimes of nonlinear parity-time (PT) symmetric laser composed of two coupled fiber cavities. We find that power-dependent nonlinear phase shifters broaden regions of existence of both PT-symmetric and PT-broken modes, and can facilitate transitions between modes of different types. We show the existence of non-stationary regimes and demonstrate an ambiguity of the transition process for some of the unstable states. We also identify the presence of higher-order stationary modes, which return to the initial state periodically after a certain number of round-trips.

Bioactive Coatings Formed on Titanium by Plasma Electrolytic Oxidation: Composition and Properties.

Bioactive coatings on VT1-0 commercially pure titanium were formed by the plasma electrolytic oxidation (PEO). A study of the morphological features of coatings was carried out using scanning electron microscopy. A composition of formed coatings was investigated using energy-dispersive spectroscopy and X-ray diffractometry analysis. It was shown that PEO-coatings have calcium phosphate in their composition, which increases the bioactivity of the surface layer. Electrochemical properties of the samples were studied by potentiondynamic polarization and electrochemical impedance spectroscopy in different physiological media: simulated body fluid and minimum essential medium. The data of electrochemical studies indicate more than 15 times decrease in the corrosion current density for the sample with coating (5.0 × 10-9 A/cm2) as compared to the bare titanium (7.7 × 10-8 A/cm2). The formed PEO-layers have elastoplastic properties close to human bone (12-30 GPa) and a lower friction coefficient in comparison with bare metal. The wettability of PEO-layers increased. The contact angle for formed coatings reduced by more than 60° in comparison with bare metal (from 73° for titanium to 8° for PEO-coating). Such an increase in surface hydrophilicity contributes to the greater biocompatibility of the formed coating in comparison with commercially pure titanium. PEO can be prospective as a method for improving titanium surface bioactivity.

How to Stimulate Myocardial Regeneration in Adult Mammalian Heart: Existing Views and New Approaches.

Stem cell-based therapy has been considered as a promising option in the treatment of ischemic heart disease. Although stem cell administration resulted in the temporary improvement of myocardial contractility in the majority of studies, the formation of new cardiomyocytes within the injured myocardium has not been conclusively demonstrated. Consequently, the focus of research in the field has since shifted to stem cell-derived paracrine factors, including cytokines, growth factors, mRNA, and miRNA. Notably, both mRNA and miRNA can enter into the extracellular space either in soluble form or packed into membrane vesicles. Stem cell-derived paracrine factors have been shown to suppress inflammation and apoptosis, stimulate angiogenesis, and amplify the proliferation and differentiation of resident cardiac stem cells (CSCs). Such features have led to exosomes being considered as potential drug candidates affording myocardial regeneration. The search for chemical signals capable of stimulating cardiomyogenesis is ongoing despite continuous debates regarding the ability of mature cardiomyocytes to divide or dedifferentiate, transdifferentiation of other cells into cardiomyocytes, and the ability of CSCs to differentiate into cardiomyocytes. Future research is aimed at identifying novel cell candidates capable of differentiating into cardiomyocytes. The observation that CSCs can undergo intracellular development with the formation of "cell-in-cell structure" and subsequent release of transitory amplifying cells with the capacity to differentiate into cardiomyocytes may provide clues for stimulating regenerative cardiomyogenesis.

Age-Related Impaired Efficacy of Bone Marrow Cell Therapy for Myocardial Infarction Reflects a Decrease in B Lymphocytes.

Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) improves post-MI cardiac function in rodents. However, clinical trials of BMC therapy have been less effective. While most rodent experiments use young healthy donors, patients undergoing autologous cell therapy are older and post-MI. We previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, and that donor MI induces inflammatory changes in BMC composition including reduced levels of B lymphocytes. Here, we hypothesized that B cell alterations in bone marrow account for the reduced therapeutic potential of post-MI and aged donor BMCs. Injection of BMCs from increasingly aged donor mice resulted in progressively poorer cardiac function and larger infarct size. Flow cytometry revealed fewer B cells in aged donor bone marrow. Therapeutic efficacy of young healthy donor BMCs was reduced by depletion of B cells. Implantation of intact or lysed B cells improved cardiac function, whereas intact or lysed T cells provided only minor benefit. We conclude that B cells play an important paracrine role in effective BMC therapy for MI. Reduction of bone marrow B cells because of age or MI may partially explain why clinical autologous cell therapy has not matched the success of rodent experiments.

Frequency comb generation in SNAP bottle resonators.

We develop a theory of optical frequency comb generation in ultra-compact surface nanoscale axial photonic (SNAP) bottle microresonators, employing the nonlinear interaction of whispering gallery modes which are confined along an optical fiber with nanoscale radius variation. We predict that a SNAP microresonator with a radius of a few micrometers can generate a frequency comb with an ultra-fine sub-gigahertz spectral spacing, which would require traditional ring resonators of centimeter radius. We identify regimes of stable or quasi-periodic comb dynamics due to soliton excitation, and show that special engineering of the SNAP radius profile can be used to compensate for nonlinearity-induced dispersion.

Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction.

BACKGROUND: Circulating angiogenic cells (CACs) are peripheral blood cells whose functional capacity inversely correlates with cardiovascular risk and that have therapeutic benefits in animal models of cardiovascular disease. However, donor age and disease state influence the efficacy of autologous cell therapy. We sought to determine whether age or coronary artery disease (CAD) impairs the therapeutic potential of CACs for myocardial infarction (MI) and whether the use of ex vivo gene therapy to overexpress endothelial nitric oxide (NO) synthase (eNOS) overcomes these defects. METHODS AND RESULTS: We recruited 40 volunteers varying by sex, age (< or ≥45 years), and CAD and subjected their CACs to well-established functional tests. Age and CAD were associated with reduced CAC intrinsic migration (but not specific response to vascular endothelial growth factor, adherence of CACs to endothelial tubes, eNOS mRNA and protein levels, and NO production. To determine how CAC function influences therapeutic potential, we injected the 2 most functional and the 2 least functional CAC isolates into mouse hearts post MI. The high-function isolates substantially improved cardiac function, whereas the low-function isolates led to cardiac function only slightly better than vehicle control. Transduction of the worst isolate with eNOS cDNA adenovirus increased NO production, migration, and cardiac function of post-MI mice implanted with the CACs. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities. CONCLUSIONS: Age and CAD impair multiple functions of CACs and limit therapeutic potential for the treatment of MI. eNOS gene therapy in CACs from older donors or those with CAD has the potential to improve autologous cell therapy outcomes.

Reflectionless potentials for slow whispering gallery modes in surface nanoscale axial photonic fiber resonators.

We consider an optical fiber with a nanoscale variation of the effective fiber radius that supports whispering gallery modes slowly propagating along the fiber, and reveal that the radius variation can be designed to support the reflectionless propagation of these modes. We show that reflectionless modulations can realize control of the transmission amplitude and temporal delay, while enabling close packing due to the absence of cross talk, in contrast to the conventional potentials.

SAW tags for the 6-GHz range.

The possibility of using 6-GHz frequencies for passive SAW tags is discussed. An example of an inline 6-GHz SAW tag design is presented. Supposing that an ultrawide frequency bandwidth B = 775 MHz can be used, the tag dimensions can be significantly reduced and the loss of reflected response remains at an acceptable level of around 50 dB. The devices were manufactured using E-beam lithography and, probed on wafer, show performance close to predicted, including the loss level of approximately 55 dB. The possibility of high-throughput manufacturing by combining nano-imprint and e-beam lithography is discussed.

Introduction into PPPM as a new paradigm of public health service: an integrative view.

In the present state of healthcare, usual medical care is generally given to the already diseased person, while the key link-personal health monitoring underlain by predictive, preventive, and personalised medicine (PPPM) techniques that are being intensively elaborated worldwide-is simply missing. It is this link, based on the recognition of subclinical conditions, prediction, and further preventive measures, that is capable of regulating morbidity and diminishing the rates of disability among able-bodied population, thus significantly cutting the traditionally high costs of treating the already diseased people. To achieve the above-mentioned goal-the elaboration of the PPPM concept and its practical implementation-it is necessary to create a fundamentally new strategy based upon the subclinical recognition of the signs-bioindicators of cryptic abnormalities long before the disease clinically manifests itself. The implementation of PPPM programme requires an adjusted technology for the proper interpretation of diagnostic data, which would allow for the current 'physician-patient' model to be gradually replaced by a novel model, 'medical advisor-healthy men-at-risk'. This is the reason for an additional need in organising combinatorial scientific, clinical, training and educational projects in the area of PPPM to elicit the content of this new branch of medicine.

Nonlocality in PT-symmetric waveguide arrays with gain and loss.

We demonstrate that light propagation in waveguide arrays that include PT-symmetric structures can exhibit strongly nonlocal sensitivity to topology of the array at fixed other parameters. We consider an array composed of lossless waveguides, that includes a pair of PT-symmetric waveguides with balanced gain and loss, and reveal that PT-symmetry breaking thresholds are different for planar and circular array configurations. These results demonstrate that PT-symmetric structures can offer new regimes for optical beam shaping compared to conservative structures.

Solitons in a chain of parity-time-invariant dimers.

Dynamics of a chain of interacting parity-time-invariant nonlinear dimers is investigated. A dimer is built as a pair of coupled elements with equal gain and loss. A relation between stationary soliton solutions of the model and solitons of the discrete nonlinear Schrödinger (DNLS) equation is demonstrated. Approximate solutions for solitons whose width is large in comparison to the lattice spacing are derived, using a continuum counterpart of the discrete equations. These solitons are mobile, featuring nearly elastic collisions. Stationary solutions for narrow solitons, which are immobile due to the pinning by the effective Peierls-Nabarro potential, are constructed numerically, starting from the anticontinuum limit. The solitons with the amplitude exceeding a certain critical value suffer an instability leading to blowup, which is a specific feature of the nonlinear parity-time-symmetric chain, making it dynamically different from DNLS lattices. A qualitative explanation of this feature is proposed. The instability threshold drops with the increase of the gain-loss coefficient, but it does not depend on the lattice coupling constant, nor on the soliton's velocity.

Autoimmunity, infectious immunity, and atherosclerosis.

INTRODUCTION: Vascular inflammation is common in certain systemic autoimmune diseases and contributes to the oxidation of low-density lipoprotein (oxLDL) and oxLDL/beta2-glycoprotein I (beta2GPI) complex formation. These complexes have been implicated as proatherogenic autoantigens that participate in the development of atherosclerotic disease. DISCUSSION: We have demonstrated that the in vitro macrophage uptake of oxLDL/beta2GPI complexes increases in the presence of IgG anti-beta2GPI antibodies and that IgG immune complexes containing oxLDL/beta2GPI upregulate the expression of both scavenger and Fcgamma receptors to activate beta2GPI specific T cells. Some persistent infections may cause immune responses that promote atherogenesis. Cellular immunity (Th1) against Helicobacter pylori (H. pylori) derived heat shock protein 60 (Hp-HSP60) cross-reacts with endogenous HSP60 to cause cardiovascular disease likely by molecular mimicry. CONCLUSION: Infectious cellular response may be proatherogenic,while the humoral response (antibody production) maybe protective. We review the recent progress in our understanding of autoimmunity and infectious immunity that promote atherosclerosis.

Recognition and degradation of myelin basic protein peptides by serum autoantibodies: novel biomarker for multiple sclerosis.

The pathologic role of autoantibodies in autoimmune disease is widely accepted. Recently, we reported that anti-myelin basic protein (MBP) serum Abs from multiple sclerosis (MS) patients exhibit proteolytic activity toward the autoantigen. The aim of this study is to determine MBP epitopes specific for the autoantibodies in MS and compare these data with those from other neuronal disorders (OND), leading to the generation of new diagnostic and prognostic criteria. We constructed a MBP-derived recombinant "epitope library" covering the entire molecule. We used ELISA and PAGE/surface-enhanced laser desorption/ionization mass spectroscopy assays to define the epitope binding/cleaving activities of autoantibodies isolated from the sera of 26 MS patients, 22 OND patients, and 11 healthy individuals. The levels of autoantibodies to MBP fragments 48-70 and 85-170 as well as to whole MBP and myelin oligodendrocyte glycoprotein molecules were significantly higher in the sera of MS patients than in those of healthy donors. In contrast, selective reactivity to the two MBP fragments 43-68 and 146-170 distinguished the OND and MS patients. Patients with MS (77% of progressive and 85% of relapsing-remitting) but only 9% of patients with OND and no healthy donors were positive for catalysis, showing pronounced epitope specificity to the encephalitogenic MBP peptide 81-103. This peptide retained its substrate properties when flanked with two fluorescent proteins, providing a novel fluorescent resonance energy transfer approach for MS studies. Thus, anti-MBP autoantibody-mediated, epitope-specific binding and cleavage may be regarded as a specific characteristic of MS compared with OND and healthy donors and may serve as an additional biomarker of disease progression.

Postinfectious immunodeficiency and autoimmunity: pathogenic and clinical values and implications.

Autoimmunity is still a mystery of clinical immunology and medicine as a whole. The etiology and pathogenesis of autoimmune disorders remain unclear and, thus, are assessed as a balance between hereditary predisposition, triggering factors and the appearance of autoantibodies and/or self-reactive T cells. Among the immunological armamentarium, molecular mimicry, based on self-reactive T- and B-cell activation by cross-reactive epitopes of infectious agents, is of special value. Hypotheses regarding the possible involvement of molecular mimicry in the development of postinfectious autoimmunity are currently very intriguing. They provide new approaches for identifying etiological agents that are associated with postinfectious autoimmunity, paired microbial- and tissue-linked epitopes targeted for autoimmune reaction determination, postinfectious autoimmunity pathogenesis recognition and specific prevention, and therapy for autoimmune disorder development.

Catalytic autoantibodies in clinical autoimmunity and modern medicine.

Abzymes (catalytic autoantibodies) belong to an absolutely new group of physiologically active substances with dual characteristics: they represent a pool of canonical autoantibodies and possess catalytic activity. Among them, proteolytic and DNA-hydrolyzing autoantibodies are of special value. Abzymes are an important pathogenic factor in the progression of clinical autoimmunity syndrome. The presence of autoantibodies against various autoantigens is accompanied by their high catalytic potential. The increase in this activity correlates with serum levels of the autoantibodies, clinical manifestations of autoimmune disorders, disease severity and the rate of progressing disability. Abzymes are crucial for immune homeostasis regulation. They can be of practical value in the development of modern immunodiagnostic tools and schedules of immunotherapy.

Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen.

Autoantibody-mediated tissue destruction is among the main features of organ-specific autoimmunity. This report describes "an antibody enzyme" (abzyme) contribution to the site-specific degradation of a neural antigen. We detected proteolytic activity toward myelin basic protein (MBP) in the fraction of antibodies purified from the sera of humans with multiple sclerosis (MS) and mice with induced experimental allergic encephalomyelitis. Chromatography and zymography data demonstrated that the proteolytic activity of this preparation was exclusively associated with the antibodies. No activity was found in the IgG fraction of healthy donors. The human and murine abzymes efficiently cleaved MBP but not other protein substrates tested. The sites of MBP cleavage determined by mass spectrometry were localized within immunodominant regions of MBP. The abzymes could also cleave recombinant substrates containing encephalytogenic MBP(85-101) peptide. An established MS therapeutic Copaxone appeared to be a specific abzyme inhibitor. Thus, the discovered epitope-specific antibody-mediated degradation of MBP suggests a mechanistic explanation of the slow development of neurodegeneration associated with MS.