Bioactive peptides based on diversity libraries, supramolecular chemistry and rational design: A new class of peptide drugs. Introduction

A new class of pharmaceutical molecules--synthetic vaccines, synthetic diagnostics and peptide drugs--are emerging based on recent advances of peptide libraries, supramolecular chemistry and rational design. The molecules of this growing class have exciting potential, not met by classical drugs based on small molecules or recombinant proteins.     

Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons

Background

A recent human clinical trial of an Alzheimer's disease (AD) vaccine using amyloid beta (Aβ) 1–42 plus QS-21 adjuvant produced some positive results, but was halted due to meningoencephalitis in some participants. The development of a vaccine with mutant Aβ peptides that avoids the use of an adjuvant may result in an effective and safer human vaccine.

Results

All peptides tested showed high antibody responses, were long-lasting, and demonstrated good memory response. Epitope mapping indicated that peptide mutation did not lead to epitope switching. Mutant peptides induced different inflammation responses as evidenced by cytokine profiles. Ig isotyping indicated that adjuvant-free vaccination with peptides drove an adequate Th2 response. All anti-sera from vaccinated mice cross-reacted with human Aβ in APP/PS1 transgenic mouse brain tissue.

Conclusion

Our study demonstrated that an adjuvant-free vaccine with different Aβ peptides can be an effective and safe vaccination approach against AD. This study represents the first report of adjuvant-free vaccines utilizing Aβ peptides carrying diverse mutations in the T-cell epitope. These largely positive results provide encouragement for the future of the development of human vaccinations for AD.     

Detection of Cancer Cell Death Mediated by a Synthetic Granzyme B-like Peptide Fluorescent Conjugate and the same Peptide Binding in Bacteria

Granzyme-mediated apoptosis, supported by pore-forming perforin, plays an important role in CD8+ T lymphocytes (CTL)-dependent cellular immunity protection against both cancer and viral infection. Quantitative and qualitative problems with CTL are potential contributing factors to disease progression. The feasibility of developing CTL-independent cellular immunity is desired but must first overcome the barrier of CTL-independent target cell recognition. Granzyme B with its strong pro-apoptotic activity in many different target cells is investigated for use in the CTL-independent cellular immunity approach, and granzyme B or its bioactive peptides without the enzymatic activity are more desirable for use. Native granzyme B with enzymatic activity is usually investigated in cancer cells for its mediation of apoptosis by detection of DNA fragmentation. Detection of cell death mediated by such peptides in cancer cells is needed to demonstrate the potential therapeutic purposes. We show with never-before-seen microscopic images using fluorescence microscopy that a synthetic granzyme B-like peptide fluorescent conjugate (GP1R) can: 1) mediate cell death of different cancer cells via membrane extrusion, 2) bind to constitutively expressed binding targets in different cancer cells and bacteria, and 3) promote bacterial phagocytosis. The putative binding targets may serve as a universal pathologic biomarker detectable by GP1R. Our data taken together demonstrate the potential applications of GP1R for use in CTL-independent target cell recognition and target cell death induction. It may lead to development of rapid targeted detection and new treatment of cancer, viral and bacterial infections. The new treatment may show mutual benefits for two or more diseases.     

DNA vaccine containing the mycobacterial hsp65 gene prevented insulitis in MLD-STZ diabetes

Background  

Our group previously demonstrated that a DNA plasmid encoding the mycobacterial 65-kDa heat shock protein (DNA-HSP65) displayed prophylactic and therapeutic effect in a mice model for tuberculosis. This protection was attributed to induction of a strong cellular immunity against HSP65. As specific immunity to HSP60 family has been detected in arthritis, multiple sclerosis and diabetes, the vaccination procedure with DNA-HSP65 could induce a cross-reactive immune response that could trigger or worsen these autoimmune diseases.     

Paratuberculosis control: a review with a focus on vaccination

Mycobacterium avium subsp. paratuberculosis (MAP) infection causes in ruminants a regional chronic enteritis that is increasingly being recognized as a significant problem affecting animal health, farming and the food industry due to the high prevalence of the disease and to recent research data strengthening the link between the pathogen and human inflammatory bowel disease (IBD). Control of the infection through hygiene-management measures and test and culling of positive animals has to date not produced the expected results and thus a new focus on vaccination against this pathogen is necessary. This review summarizes all vaccination studies of cattle, sheep or goats reporting production, epidemiological or pathogenetic effects of vaccination published before January 2010 and that provide data amenable to statistical analyses. The meta analysis run on the selected data, allowed us to conclude that most studies included in this review reported that vaccination against MAP is a valuable tool in reducing microbial contamination risks of this pathogen and reducing or delaying production losses and pathogenetic effects but also that it did not fully prevent infection. However, the majority of MAP vaccines were very similar and rudimentary and thus there is room for improvement in vaccine types and formulations.     

Design of Gold Nanoparticles in Dendritic Cell‐Based Vaccines

The design of effective cancer vaccines must be able to activate dendritic cells (DCs) of the innate immune system in order to induce immunity to pathogens and cancer. DCs patrol the body and once they encounter antigens, they orchestrate a complex mechanism of events and signals that can alert the adaptive immune system to action. However, DC‐based vaccines remain a challenge in part because the source and quality of antigens, the DC targeting molecule, type of adjuvant, and delivery vehicle must be optimized to induce a robust immune response. Gold nanoparticles (AuNPs) have now entered clinical trials as carriers due to their ease of functionalization with antigens, adjuvants, and targeting molecules. This progress report discusses how AuNPs can influence DC activation and maturation, as well as their potential impact on T helper (Th) differentiation. Ultimately, successful AuNP‐based DC vaccines are able to induce phagocytosis, activation/maturation, migration, T cell costimulation, and cytokine secretion, which is named AuNP‐induced DC tuning (AuNP‐DC tuning). Although at its infancy, understanding the processes of AuNP‐DC tuning will give a better understanding of how best to engineer AuNPs and will redefine the next generation of DC‐based vaccines.     

Thiol-Capped Gold Nanoparticle Biosensors for Rapid and Sensitive Visual Colorimetric Detection of <Emphasis Type="Italic">Klebsiella pneumoniae</Emphasis>

In the last few years, gold nanoparticle biosensors have been developed for rapid, precise, easy and inexpensive with high specificity and sensitivity detection of human, plant and animal pathogens. Klebsiella pneumoniae serotype K2 is one of the common gram-negative pathogens with high prevalence. Therefore, it is essential to provide the effective and exclusive method to detect the bacteria. Klebsiella pneumoniae serotype K2 strain ATCC9997 genomic DNA was applied to establish the detection protocol either with thiol-capped oligonucleotide probes and gold nanoparticles or polymerase chain reaction based on K2A gene sequence. In the presence of the genomic DNA and oligonucleotide probes, a change in the color of gold nanoparticles and maximum changes in wavelength at 550-650 nm was achieved. In addition, the result showed specificity of 15?×?10⁵ CFU/mL and 9 pg/μL by gold nanoparticles probes. The lower limit of detection obtained by PCR method was 1 pg/μL. Moreover, results demonstrated a great specificity of the designed primers and probes for colorimetric detection assay and PCR. Colorimetric detection using gold nanoparticle probe with advantages such as the lower time required for detection and no need for expensive detection instrumentation compared to the biochemical and molecular methods could be introduced for rapid, accurate detection of the bacteria.     

Rapid Fluorescent Detection of Escherichia coli K88 Based on DNA Aptamer Library as Direct and Specific Reporter Combined With Immuno-Magnetic Separation

Nucleic acid aptamers have long demonstrated the capacity to bind cells with high affinity so that they have been utilized to diagnose various important pathogens. In this study, a DNA aptamer library was on initial efforts developed to act as a specific reporter for rapid detection of enter toxigenic Escherichia coli (ETEC) K88 combined with immuno-magnetic separation (IMS). During a Whole-cell Systematic Evolution of Ligands by Exponential Enrichment (CELL-SELEX) procedure, the last selection pool against ETEC K88, which is named “DNA aptamer library” here, was selected and subsequently identified by flow cytometric analysis and confocal imaging. A K88 monoclonal antibody (mAb) with high affinity (K_aff: 1.616?±?0.033?×?10⁸ M^?1) against K88 fimbrial protein was prepared, biotinylated and conjugated to streptavidin-coated magnetic beads (MBs). After the bacteria were effectively captured and enriched from the complex sample by immuno-magnetic beads (IMBs), 5′-FITC modified aptamer library was directly bound to target cells as a specific reporter for its detection. The detection system showed clearly high specificity and sensitivity with the detection limit of 1.1?×?10³ CFU/ml in pure culture and 2.2?×?10³ CFU/g in artificially contaminated fecal sample. The results also indicated that fluorophore-lablled DNA aptamer library as specific reporter could generate more reliable signals than individual aptamer with best affinity against target cells and implied it would have great applied potential in directly reporting bacteria from complex samples combined with IMS technology.     

High-performance low field MRI enables visualization of persistent pulmonary damage after COVID-19

The outbreak of coronavirus disease 2019 (COVID-19) with the origin of the spread assumed to be located in Wuhan, China, began in December 2019, and is continuing until now. With the COVID-19 pandemic showing a progressive spread throughout the countries of the world, there is emerging interest for the potential long-term consequences of suffering from a COVID-19 pneumonia. Imaging plays a central role in the diagnosis and management of COVID-19 pneumonia, with chest X-ray examinations and computed tomography (CT) being undoubtedly the modalities most widely used, allowing for a fast and sensitive detection of infiltration patterns associated with COVID-19 pneumonia. For a better understanding of underlying pathomechanisms of pulmonary damage, longitudinal imaging series are warranted, for which CT is of limited usability due to repeated exposure of X-rays. Recent advances in MRI suggested that high-performance low-field MRI might represent a valuable method for pulmonary imaging without the need of radiation exposure. However, so far, low-field MRI has not been applied to study pulmonary damage after COVID-19 pneumonia. We present a case report of a patient who suffered from COVID-19 pneumonia using 0.55 T MRI for follow-up examinations three months after initial infection. Low-field MRI enables a precise visualization of persistent pulmonary changes including ground-glass opacities, which are consistent with CT performed on the same day. Low-field MRI seems to be feasible in the detection of pulmonary involvement in patients with COVID-19 pneumonia and may have the potential for repetitive lung examinations in monitoring the reconvalescence after pulmonary infections.     

Antigenized antibodies expressing Vbeta8.2 TCR peptides immunize against rat experimental allergic encephalomyelitis

BACKGROUND: Immunity against the T cell receptor (TCR) is considered to play a central role in the regulation of experimental allergic encephalomyelitis (EAE), a model system of autoimmune disease characterized by a restricted usage of TCR genes. Methods of specific vaccination against the TCR of pathogenetic T cells have included attenuated T cells and synthetic peptides from the sequence of the TCR. These approaches have led to the concept that anti-idiotypic immunity against antigenic sites of the TCR, which are a key regulatory element in this disease. METHODS: The present study in the Lewis rat used a conventional idiotypic immunization based on antigenized antibodies expressing selected peptide sequences of the Vbeta8.2 TCR (93ASSDSSNTE101 and 39DMGHGLRLIHYSYDVNSTEKG59). RESULTS: The study demonstrates that vaccination with antigenized antibodies markedly attenuates, and in some instances, prevents clinical EAE induced with the encephalitogenic peptide 68GSLPQKSQRSQDENPVVHF88 in complete Freunds' adjuvant (CFA). Antigenized antibodies induced an anti-idiotypic response against the Vbeta8.2 TCR, which was detected by ELISA and flowcytometry. No evidence was obtained of a T cell response against the corresponding Vbeta8.2 TCR peptides. CONCLUSIONS: The results indicate that antigenized antibodies expressing conformationally-constrained TCR peptides are a simple means to induce humoral anti-idiotypic immunity against the TCR and to vaccinate against EAE. The study also suggests the possibility to target idiotypic determinants of TCR borne on pathogenetic T cells to vaccinate against disease.     

Antigenized antibodies expressing Vβ8.2 TCR peptides immunize against rat experimental allergic encephalomyelitis

Background  

Immunity against the T cell receptor (TCR) is considered to play a central role in the regulation of experimental allergic encephalomyelitis (EAE), a model system of autoimmune disease characterized by a restricted usage of TCR genes. Methods of specific vaccination against the TCR of pathogenetic T cells have included attenuated T cells and synthetic peptides from the sequence of the TCR. These approaches have led to the concept that anti-idiotypic immunity against antigenic sites of the TCR, which are a key regulatory element in this disease.     

Structure-based design of new poly (ADP-ribose) polymerase (PARP-1) inhibitors

Poly (ADP-ribose) polymerase (PARP-1) is a well-established nuclear protein with prominent role in signaling and DNA repair. Various clinical candidates have been identified with the role in PARP-1 inhibition. Based on the pharmacophoric features identified from previous studies and molecular docking interactions, thiazolidine-2,4-dione derivatives have been evaluated for their PARP inhibitory activity. From an in vitro assay, 5-((1-(4-isopropylbenzyl)-1H-indol-3-yl)methylene)thiazolidine-2,4-dione (16) was identified as a potent inhibitor having low micromolar inhibitory activity \((\hbox {IC}_{50} \,{=}\, 0.74 \,\pm \, 0.25\,\upmu \hbox {M})\). Thus, a structure-based design approach utilized in the present study helped to identify thiazolidine-2,4-dione as a novel scaffold against PARP-1 for potential development of potent anticancer therapeutics.     

Granulocyte-macrophage colony-stimulating factor as an immune-based therapy in HIV infection

The HIV/AIDS epidemic continues to spread despite more than 20 years of significant research and major advances in its treatment. The introduction of highly active antiretroviral therapy in recent years has significantly improved disease treatment with a dramatic impact in HIV/AIDS associated morbidity and mortality in countries which have access to this therapy. Despite these advances, such therapies are imperfect and other therapeutic modalities, including immune-based therapies, are being actively sought. Potential benefits of immune-based therapies include: 1) the improvement of HIV-specific immunity to enhance control of viral replication, 2) the improvement of other aspects of host immunity in order to prevent or delay the development of opportunistic infections and 3) the potential to purge virus from cellular reservoirs which are sustained despite the effects of potent antiretroviral therapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been studied as one of these immune-based therapies. Several randomized, controlled trials have demonstrated benefits of using GM-CSF as an adjunct to conventional anti-retroviral therapy, although such benefits have not been universally observed. Individual studies have shown that GM-CSF increases CD4+ T cells counts and may be associated with decreased plasma HIV RNA levels. There is limited evidence that GM-CSF may help prevent the emergence of antiretroviral drug resistant viruses and that it may decrease the risk of infection in advanced HIV disease. Despite its high costs and the need to be administered subcutaneously, encouraging results continue to emerge from further studies, suggesting that GM-CSF has the potential to become an effective agent in the treatment of HIV infection.     

Effect of vaccination against COVID-19 spreading

We continue (Ref. 1: Proc. Jpn. Acad. Ser. B 97, 22–49) to analyze the COVID-19 status. We concentrate on the following issues in this work:1. Effect of vaccination against the spreading of SARS-CoV-2.2. General landscape of the world situation concerning vaccinations.3. Some aspects of the new variants of SARS-CoV-2.Our findings include:1. With vaccinations, it is fair to say that we have entered a new phase in the fight against the virus SARS-CoV-2. We have analyzed some preliminary data to find how vaccinations can be effective against COVID-19 spreading. This analysis is based on, and is a continuation of, our first paper quoted in Ref. 1.2. If Tokyo (or Japan) continues to keep its vaccination schedule (starting in early April, 2021 and finishing it for elderly, 65 or older, in 4 months), it will see a sign of control of the virus in early June, 2021 although we see changes of this status due to new, more contagious variants.3. The strength (parameter β) of a new contagious variant can be estimated based on the initial data on the variant (Section 5).     

Effects of Vaccination Efficacy on Wealth Distribution in Kinetic Epidemic Models

The spread of the COVID-19 pandemic has highlighted the close link between economics and health in the context of emergency management. A widespread vaccination campaign is considered the main tool to contain the economic consequences. This paper will focus, at the level of wealth distribution modeling, on the economic improvements induced by the vaccination campaign in terms of its effectiveness rate. The economic trend during the pandemic is evaluated, resorting to a mathematical model joining a classical compartmental model including vaccinated individuals with a kinetic model of wealth distribution based on binary wealth exchanges. The interplay between wealth exchanges and the progress of the infectious disease is realized by assuming, on the one hand, that individuals in different compartments act differently in the economic process and, on the other hand, that the epidemic affects risk in economic transactions. Using the mathematical tools of kinetic theory, it is possible to identify the equilibrium states of the system and the formation of inequalities due to the pandemic in the wealth distribution of the population. Numerical experiments highlight the importance of the vaccination campaign and its positive effects in reducing economic inequalities in the multi-agent society.     

Photonics for microwave measurements

As an emerging topic, photonic‐assisted microwave measurements with distinct features such as wide frequency coverage, large instantaneous bandwidth, low frequency‐dependent loss, and immunity to electromagnetic interference, have been extensively studied recently. In this article, we provide a comprehensive overview of the latest advances in photonic microwave measurements, including microwave spectrum analysis, instantaneous frequency measurement, microwave channelization, Doppler frequency‐shift measurement, angle‐of‐arrival detection, time–frequency analysis, compressive sensing, and phase‐noise measurement. A photonic microwave radar, as a functional measurement system, is also reviewed. The performance of the photonic measurement solutions is evaluated and compared with the electronic solutions. Future prospects using photonic integrated circuits and software‐defined architectures to further improve the measurement performance are also discussed.

     

Epidemic spreading on networks with vaccination

In this paper, a new susceptible-infected-susceptible (SIS) model on complex networks with imperfect vaccination is proposed. Two types of epidemic spreading patterns (the recovered individuals have or have not immunity) on scale-free networks are discussed. Both theoretical and numerical analyses are presented. The epidemic thresholds related to the vaccination rate, the vaccination-invalid rate and the vaccination success rate on scale-free networks are demonstrated, showing different results from the reported observations. This reveals that whether or not the epidemic can spread over a network under vaccination control is determined not only by the network structure but also by the medicine's effective duration. Moreover, for a given infective rate, the proportion of individuals to vaccinate can be calculated theoretically for the case that the recovered nodes have immunity. Finally, simulated results are presented to show how to control the disease prevalence.     

The mucosal immune system: From dentistry to vaccine development

The oral cavity is the beginning of the aero-digestive tract, which is covered by mucosal epithelium continuously under the threat of invasion of pathogens, it is thus protected by the mucosal immune system. In the early phase of our scientific efforts for the demonstration of mucosal immune system, dental science was one of major driving forces due to their foreseeability to use oral immunity for the control of oral diseases. The mucosal immune system is divided functionally into, but interconnected inductive and effector sites. Intestinal Peyer’s patches (PPs) are an inductive site containing antigen-sampling M cells and immunocompetent cells required to initiate antigen-specific immune responses. At effector sites, PP-originated antigen-specific IgA B cells become plasma cells to produce polymeric IgA and form secretory IgA by binding to poly-Ig receptor expressed on epithelial cells for protective immunity. The development of new-generation mucosal vaccines, including the rice-based oral vaccine MucoRice, on the basis of the coordinated mucosal immune system is a promising strategy for the control of mucosal infectious diseases.     

CMOS and beyond

Lithography has played a key role in the scaling of CMOS-based integrated circuits. To fabricate sub-70 nm features, new techniques based on electron projection and extreme ultraviolet radiation are being developed. These and other lithographic solutions are discussed. For the ultimate in scaling, an alternate approach would be to start with objects that are inherently nano-scale in size, and use chemical techniques to have these objects self-assemble into units that provide electronic functionality. Several classes of molecules, including carbon nanotubes, deoxyribonucleic acid (DNA) and custom-synthesized organic molecules, are potentially suitable for this approach. Some recent advances in their research will be reviewed.     

Emerging methods and tools for environmental risk assessment, decision-making, and policy for nanomaterials: summary of NATO Advanced Research Workshop

Nanomaterials and their associated technologies hold promising opportunities for the development of new materials and applications in a wide variety of disciplines, including medicine, environmental remediation, waste treatment, and energy conservation. However, current information regarding the environmental effects and health risks associated with nanomaterials is limited and sometimes contradictory. This article summarizes the conclusions of a 2008 NATO workshop designed to evaluate the wide-scale implications (e.g., benefits, risks, and costs) of the use of nanomaterials on human health and the environment. A unique feature of this workshop was its interdisciplinary nature and focus on the practical needs of policy decision makers. Workshop presentations and discussion panels were structured along four main themes: technology and benefits, human health risk, environmental risk, and policy implications. Four corresponding working groups (WGs) were formed to develop detailed summaries of the state-of-the-science in their respective areas and to discuss emerging gaps and research needs. The WGs identified gaps between the rapid advances in the types and applications of nanomaterials and the slower pace of human health and environmental risk science, along with strategies to reduce the uncertainties associated with calculating these risks.