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.     

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.     

Prospects for control of emerging infectious diseases with plasmid DNA vaccines

Experiments almost 20 years ago demonstrated that injections of a sequence of DNA encoding part of a pathogen could stimulate immunity. It was soon realized that "DNA vaccination" had numerous potential advantages over conventional vaccine approaches including inherent safety and a more rapid production time. These and other attributes make DNA vaccines ideal for development against emerging pathogens. Recent advances in optimizing various aspects of DNA vaccination have accelerated this approach from concept to reality in contemporary human trials. Although not yet licensed for human use, several DNA vaccines have now been approved for animal health indications. The rapid manufacturing capabilities of DNA vaccines may be particularly important for emerging infectious diseases including the current novel H1N1 Influenza A pandemic, where pre-existing immunity is limited. Because of recent advances in DNA vaccination, this approach has the potential to be a powerful new weapon in protecting against emerging and potentially pandemic human pathogens.     

Rational behavior is a ‘double-edged sword’ when considering voluntary vaccination

Of particular importance for public health is how to understand strategic vaccination behavior in social networks. Social learning is a central aspect of human behavior, and it thus shapes vaccination individuals’ decision-making. Here, we study two simple models to address the impact of the more rational decision-making of individuals on voluntary vaccination. In the first model, individuals are endowed with memory capacity for their past experiences of dealing with vaccination. In addition to their current payoffs, they also take account of the historical payoffs that are discounted by a memory-decaying factor. They use such overall payoffs (weighing the current payoffs and historical payoffs) to reassess their vaccination strategies. Those who have higher overall payoffs are more likely imitated by their social neighbors. In the second model, individuals do not blindly learn the strategies of neighbors; they also combine the fraction of infection in the past epidemic season. If the fraction of infection surpasses the perceived risk threshold, individuals will increase the probability of taking vaccination. Otherwise, they will decrease the probability of taking vaccination. Then we use evolutionary game theory to study the vaccination behavior of people during an epidemiological process. To do this, we propose a two-stage model: individuals make vaccination decisions during a yearly vaccination campaign, followed by an epidemic season. This forms a feedback loop between the vaccination decisions of individuals and their health outcomes, and thus payoffs. We find that the two more rational decision-making models have nontrivial impacts on the vaccination behavior of individuals, and, as a result, on the final fraction of infection. Our results highlight that, from an individual’s viewpoint, the decisions are optimal and more rational. However, from the social viewpoint, the strategies of individuals can give rise to distinct outcomes. Namely, the rational behavior of individuals plays a ‘double-edged-sword’ role on the social effects.     

Epidemiological impact of waning immunization on a vaccinated population

This is an epidemiological SIRV model based study that is designed to analyze the impact of vaccination in containing infection spread, in a 4-tiered population compartment comprised of susceptible, infected, recovered and vaccinated agents. While many models assume a lifelong protection through vaccination, we focus on the impact of waning immunization due to conversion of vaccinated and recovered agents back to susceptible ones. Two asymptotic states exist, the “disease-free equilibrium” and the “endemic equilibrium” and we express the transitions between these states as function of the vaccination and conversion rates and using the basic reproduction number. We find that the vaccination of newborns and adults have different consequences on controlling an epidemic. Also, a decaying disease protection within the recovered sub-population is not sufficient to trigger an epidemic at the linear level. We perform simulations for a parameter set mimicking a disease with waning immunization like pertussis. For a diffusively coupled population, a transition to the endemic state can proceed via the propagation of a traveling infection wave, described successfully within a Fisher-Kolmogorov framework.     

Assessment of immune response to repeat stimulation with BCG vaccine using in vitro PBMC model

Background  

Tuberculosis (TB) is one of the most prevalent cause of death due to a single pathogen. Bacillus Calmette Guérin (BCG) is the only vaccine available for clinical use that protects against miliary TB; however, this vaccine has shown variable levels of efficacy against pulmonary TB. In India, a single dose of BCG vaccine is given and there are few countries where repeated doses of BCG are given. The incidence of TB in India is very high inspite of primary vaccination in neonatal period and therefore requires consideration for repeated immunization.     

Struggle for space: viral extinction through competition for cells

The design of protocols to suppress the propagation of viral infections is an enduring enterprise, especially hindered by limited knowledge of the mechanisms leading to viral extinction. Here we report on infection extinction due to intraspecific competition to infect susceptible hosts. Beneficial mutations increase the production of viral progeny, while the host cell may develop defenses against infection. For an unlimited number of host cells, a feedback runaway coevolution between host resistance and progeny production occurs. However, physical space limits the advantage that the virus obtains from increasing offspring numbers; thus, infection clearance may result from an increase in host defenses beyond a finite threshold. Our results might be relevant to devise improved control strategies in environments with mobility constraints or different geometrical properties.     

Vaccine based on a ubiquitous cysteinyl protease and streptococcal pyrogenic exotoxin A protects against Streptococcus pyogenes sepsis and toxic shock

Background

The gram-positive bacterium Streptococcus pyogenes is a common pathogen of humans that causes invasive infections, toxic-shock syndrome, rheumatic fever, necrotizing fasciitis and other diseases. Detection of antibiotic resistance in clinical isolates has renewed interest in development of new vaccine approaches for control S. pyogenes sepsis. In the study presented, a novel protein vaccine was examined. The vaccine was based on a recombinant protein fusion between streptococcal pyrogenic exotoxin B (SpeB), a cysteinyl protease expressed by all clinical isolates, and streptococcal pyrogenic exotoxin A (SpeA), a superantigen produced by a large subset of isolates.

Results

A novel protein was produced by mutating the catalytic site of SpeB and the receptor binding surface of SpeA in a fusion of the two polypeptides. Vaccination of HLA-DQ8 transgenic mice with the SpeA-SpeB fusion protein protected against a challenge with the wild-type SpeA that was lethal to naïve controls, and vaccinated mice were protected from an otherwise lethal S. pyogenes infection.

Conclusion

These results suggest that the genetically attenuated SpeA-SpeB fusion protein may be useful for controlling S. pyogenes infections. Vaccination with the SpeA-SpeB fusion protein described in this study may potentially result in protective immunity against multiple isolates of S. pyogenes due to the extensive antibody cross-reactivity previously observed among all sequence variants of SpeB and the high frequency of SpeA-producing strains.     

Canine Olfactory Detection of a Non-Systemic Phytobacterial Citrus Pathogen of International Quarantine Significance

For millennia humans have benefitted from application of the acute canine sense of smell to hunt, track and find targets of importance. In this report, canines were evaluated for their ability to detect the severe exotic phytobacterial arboreal pathogen Xanthomonas citri pv. citri (Xcc), which is the causal agent of Asiatic citrus canker (Acc). Since Xcc causes only local lesions, infections are non-systemic, limiting the use of serological and molecular diagnostic tools for field-level detection. This necessitates reliance on human visual surveys for Acc symptoms, which is highly inefficient at low disease incidence, and thus for early detection. In simulated orchards the overall combined performance metrics for a pair of canines were 0.9856, 0.9974, 0.9257 and 0.9970, for sensitivity, specificity, precision, and accuracy, respectively, with 1–2 s/tree detection time. Detection of trace Xcc infections on commercial packinghouse fruit resulted in 0.7313, 0.9947, 0.8750, and 0.9821 for the same performance metrics across a range of cartons with 0–10% Xcc-infected fruit despite the noisy, hot and potentially distracting environment. In orchards, the sensitivity of canines increased with lesion incidence, whereas the specificity and overall accuracy was >0.99 across all incidence levels; i.e., false positive rates were uniformly low. Canines also alerted to a range of 1–12-week-old infections with equal accuracy. When trained to either Xcc-infected trees or Xcc axenic cultures, canines inherently detected the homologous and heterologous targets, suggesting they can detect Xcc directly rather than only volatiles produced by the host following infection. Canines were able to detect the Xcc scent signature at very low concentrations (10,000× less than 1 bacterial cell per sample), which implies that the scent signature is composed of bacterial cell volatile organic compound constituents or exudates that occur at concentrations many fold that of the bacterial cells. The results imply that canines can be trained as viable early detectors of Xcc and deployed across citrus orchards, packinghouses, and nurseries.     

Towards dynamic control of magnetic fields to focus magnetic carriers to targets deep inside the body

Magnetic drug delivery has the potential to target therapy to specific regions in the body, improving efficacy and reducing side effects for treatment of cancer, stroke, infection, and other diseases. Using stationary external magnets, which attract the magnetic drug carriers, this treatment is limited to shallow targets (<5 cm below skin depth using the strongest possible, still safe, practical magnetic fields). We consider dynamic magnetic actuation and present initial results that show it is possible to vary magnets one against the other to focus carriers between them on average. The many remaining tasks for deep targeting in-vivo are then briefly noted.     

Smoothly Clipped Absolute Deviation (SCAD) regularization for compressed sensing MRI Using an augmented Lagrangian scheme

PurposeCompressed sensing (CS) provides a promising framework for MR image reconstruction from highly undersampled data, thus reducing data acquisition time. In this context, sparsity-promoting regularization techniques exploit the prior knowledge that MR images are sparse or compressible in a given transform domain. In this work, a new regularization technique was introduced by iterative linearization of the non-convex smoothly clipped absolute deviation (SCAD) norm with the aim of reducing the sampling rate even lower than it is required by the conventional l₁ norm while approaching an l₀ norm.Materials and MethodsThe CS-MR image reconstruction was formulated as an equality-constrained optimization problem using a variable splitting technique and solved using an augmented Lagrangian (AL) method developed to accelerate the optimization of constrained problems. The performance of the resulting SCAD-based algorithm was evaluated for discrete gradients and wavelet sparsifying transforms and compared with its l₁-based counterpart using phantom and clinical studies. The k-spaces of the datasets were retrospectively undersampled using different sampling trajectories. In the AL framework, the CS-MRI problem was decomposed into two simpler sub-problems, wherein the linearization of the SCAD norm resulted in an adaptively weighted soft thresholding rule with a sparsity enhancing effect.ResultsIt was demonstrated that the proposed regularization technique adaptively assigns lower weights on the thresholding of gradient fields and wavelet coefficients, and as such, is more efficient in reducing aliasing artifacts arising from k-space undersampling, when compared to its l₁-based counterpart.ConclusionThe SCAD regularization improves the performance of l₁-based regularization technique, especially at reduced sampling rates, and thus might be a good candidate for some applications in CS-MRI.     

Hepatitis C virus utilizes lipid droplet for production of infectious virus

Hepatitis C virus (HCV) establishes a persistent infection and causes chronic hepatitis. Chronic hepatitis patients often develop hepatic cirrhosis and progress to liver cancer. The development of this pathological condition is linked to the persistent infection of the virus. In other words, viral replication/multiplication may contribute to disease pathology. Accumulating clinical studies suggest that HCV infection alters lipid metabolism, and thus causes fatty liver. It has been reported that this abnormal metabolism exacerbates hepatic diseases. Recently, we revealed that lipid droplets play a key role in HCV replication. Understanding the molecular mechanism of HCV replication will help elucidate the pathogenic mechanism and develop preventive measures that inhibit disease manifestation by blocking persistent infection. In this review, we outline recent findings on the function of lipid droplets in the HCV replication cycle and describe the relationship between the development of liver diseases and virus replication.     

Statistical Physics Analysis of Maximum a Posteriori Estimation for Multi-channel Hidden Markov Models

The performance of Maximum a posteriori (MAP) estimation is studied analytically for binary symmetric multi-channel Hidden Markov processes. We reduce the estimation problem to a 1D Ising spin model and define order parameters that correspond to different characteristics of the MAP-estimated sequence. The solution to the MAP estimation problem has different operational regimes separated by first order phase transitions. The transition points for L-channel system with identical noise levels, are uniquely determined by L being odd or even, irrespective of the actual number of channels. We demonstrate that for lower noise intensities, the number of solutions is uniquely determined for odd L, whereas for even L there are exponentially many solutions. We also develop a semi analytical approach to calculate the estimation error without resorting to brute force simulations. Finally, we examine the tradeoff between a system with single low-noise channel and one with multiple noisy channels.     

Ultrastructural characterization of cells in primary cultures from different adult tissues of Biomphalaria tenagophila TAIM,a strain that is absolutely resistant to Schistosoma mansoni infection

The etiological agent of schistosomiasis in Brazil, Schistosoma mansoni, requires an obligatory passage through Biomphalaria snails to complete its life cycle. In these intermediate hosts, interaction with the parasite is mediated by humoral factors and hemocytes by mechanisms that are not yet fully understood. Extant studies exploring these processes are usually conducted through experimental infection of Biomphalaria with S. mansoni miracidia. Thus, tissue-derived cultures of Biomphalaria may be useful in increasing the understanding of that interaction at cellular level. However, in the absence of morphological characterization of those cells in culture, the application of such models is delayed. In the present work, we cultured different tissues of B. tenagophila, the second most important host of S. mansoni in Brazil, using a strain that is naturally and absolutely resistant to S. mansoni infection. This decision was driven by the view that this strain might be provided with the most effective response against parasite infection. Primary cultures were successfully established from nine Biomphalaria tissues and the respective cells in culture were ultra structurally described. Attention was particularly devoted to cells derived from mantle cavity and kidney tissues. Although they have been considered important centers for hemocyte production in Biomphalaria, no detailed cell characterization is available in the pertinent literature. Herein, kidney-derived cells partially shared hematoblast characteristics. Moreover, under optical microscopy, kidney cells in culture were very similar to those derived from amebocyte-producing organ (APO) cultures, which have been recently shown to be capable of eliminating S. mansoni sporocysts in vitro. Based on the close resemblance of those cultures and their anatomical proximity inside the mantle cavity, we suggest the effective participation of Biomphalaria kidney cells in hematopoiesis and in host response to S. mansoni infection.     

CD40mAb adjuvant induces a rapid antibody response that may be beneficial in post-exposure prophylaxis

Active vaccination can be effective as a post-exposure prophylaxis, but the rapidity of the immune response induced, relative to the incubation time of the pathogen, is critical. We show here that CD40mAb conjugated to antigen induces a more rapid specific antibody response than currently used immunological adjuvants, alum and monophosphoryl lipid A™.     

基于节点度信息的自愿免疫模型研究

疾病的广泛传播给人类带来了巨大的损失, 因此抑制疾病的传播非常重要. 本文考虑了个体接种疫苗意愿的差异性, 并结合博弈理论建立了一个基于节点度信息的自愿免疫模型. 理论解析结果证明当感染率超过某个阈值时, 该模型与忽略个体接种意愿差异性的经典模型(Zhang et al 2010 New J. Phys. 12 023015) 传播效果(感染节点数)一样. 继而考虑疫苗永久有效和有效期有限两种情况, 在Barabási-Albert网络中利用SIS传播模型对疾病的传播进程进行了数值模拟, 发现数值模拟结果与理论解析结果非常符合. 实验证明, 当感染耗费和接种疫苗耗费相同时, 该模型比忽略个体接种意愿差异性的经典模型能够更好的抑制疾病的传播, 且感染人数下降比例超过65%, 更重要的是,疫苗有效期越长本文的模型 (与忽略个体接种意愿差异性的经典模型相比)抑制疾病传播效果越好. 关键词： 疾病传播 自愿免疫 接种疫苗倾向 节点度     

How to search for pentaquarks in high energy hadronic interactions

The strange-anticharmed Pentaquark is a uudc?s or uddc?s five-quark baryon that is expected to be either a narrow resonance, or possibly even stable against strong and electromagnetic decay. We describe this hyperon here, its structure, binding energy and lifetime, resonance width, production mechanisms, production cross sections, and decay modes. We describe techniques to reduce backgrounds in search experiments and to optimize the conditions for Pentaquark observation. Possibilities for enhancing the signal over background in Pentaquark searches are investgated by examining predictions for detailed momentum and angular distributions in multiparticle final states. We consider a loosely bound molecule and also a strongly-bound five-quark system. Fermilab E791 data, currently being analyzed, may have marginal statistics for showing definitive signals. Future experiments in the spirit of the recent CHARM2000 workshop, such as FNAL E781 and CERN COMPASS with 10⁶?10⁷ reconstructed charmed baryon events, should have sensitivity to determine whether or not the Pentaquark exists.     

High-spin states in 22Ne populated in the 14C(12C, α)reaction

The CDF Collaboration reported an excess in the production of two jets in association with a W . We discuss constraints on possible new particle state interpretations of this excess. The fact of no statistically significant deviation from the SM expectation for Z +dijet events in CDF data disfavors the new particle explanation. We show that the nucleon intrinsic strange quarks provide an important contribution to the W boson production in association with a single top quark production. Such W +t single top quark production can contribute to the CDF W +dijet excess, thus the nucleon intrinsic quarks can provide a possible explanation to the CDF excess in W +dijet but not in Z +dijet events.     

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).