Polysaccharide nanoparticles can efficiently modulate the immune response against anHIV peptide antigen

The development of an effective HIV vaccine continues to be a major health challenge since, so far, only the RV144 trial has demonstrated a modest clinical efficacy. Recently, the targeting of the 12 highly conserved protease cleavage sites (PCS1–12) has been presented as a strategy seeking to hamper the maturation and infectivity of HIV. To pursue this line of research, and because peptide antigens have low immunogenicity, we have included these peptides in engineered nanoparticles, aiming at overcoming this limitation. More specifically, we investigated whether the covalent attachment of a PCS peptide (PCS5) to polysaccharide-based nanoparticles, and their coadministration with polyinosinic:polycytidylic acid (poly(I:C)), improved the generated immune response. To this end, PCS5 was first conjugated to two different polysaccharides (chitosan and hyaluronic acid) through either a stable or a cleavable bond and then associated with an oppositely charged polymer (dextran sulfate and chitosan) and poly(I:C) to form the nanoparticles. Nanoparticles associating PCS5 by ionic interactions were used in this study as the control formulation. In vivo, all nanosystems elicited high anti-PCS5 antibodies. Nanoparticles containing PCS5 conjugated and poly(I:C) seemed to induce the strongest activation of antigen-presenting cells. Interestingly, T cell activation presented different kinetics depending on the prototype. These findings show that both the nanoparticle composition and the conjugation of the HIV peptide antigen may play an important role in the generation of humoral and cellular responsesThis work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Award No. R01AI111805, Subaward No. 41795-02) and by the European Union’s Horizon 2020 research program (NanoPilot project, Grant Agreement No. 646142). T.G.D. acknowledges a predoctoral FPU grant from the Spanish Ministry of Education, Culture and Sports (Grant No. FPU14/05866)S

Advances in the study of B cells in renal ischemia-reperfusion injury

Renal ischemia-reperfusion injury (IRI) is a non-negligible clinical challenge for clinicians in surgeries such as renal transplantation. Functional loss of renal tubular epithelial cell (TEC) in IRI leads to the development of acute kidney injury, delayed graft function (DGF), and allograft rejection. The available evidence indicates that cellular oxidative stress, cell death, microvascular dysfunction, and immune response play an important role in the pathogenesis of IRI. A variety of immune cells, including macrophages and T cells, are actively involved in the progression of IRI in the immune response. The role of B cells in IRI has been relatively less studied, but there is a growing body of evidence for the involvement of B cells, which involve in the development of IRI through innate immune responses, adaptive immune responses, and negative immune regulation. Therefore, therapies targeting B cells may be a potential direction to mitigate IRI. In this review, we summarize the current state of research on the role of B cells in IRI, explore the potential effects of different B cell subsets in the pathogenesis of IRI, and discuss possible targets of B cells for therapeutic aim in renal IRI

WTC2005-63258 RESEARCH ON THE IDENTIFICATION METHODS OF FRICTION IN KINEMATICAL JOINTS OF MECHANICAL SYSTEMS

ABSTRACT This paper describes two approaches for the simultaneous identification of the coulomb and viscous parameters in kinematical joints. One is a time-domain method (TDM) and the other is a frequency-domain method (FDM). Simulation shows that both of the two methods have good performances in identifying friction at high SNR (90dB). But at low SNR (20dB), the estimation accuracy of the frequency-domain method is higher than that of the time-domain method. A field experiment employing a linkage mechanism driven by motor is also carried out. The experimental results obtained by the two approaches are almost identical under different experiment conditions. It has been concluded that the presented identification methods of friction in kinematical joints are correct and applicable. INTRODUCTION Kinematical joint is an absolutely necessary structural connection in mechanical systems. The kinematical joint is responsible for transferring energy to a remote site, and may change the type of motion, as needed. The characteristics of kinematical joints have been studied in many paper

Henipavirus zoonosis: outbreaks, animal hosts and potential new emergence

Hendra virus (HeV) and Nipah virus (NiV) are biosafety level 4 zoonotic pathogens causing severe and often fatal neurological and respiratory disease. These agents have been recognized by the World Health Organization as top priority pathogens expected to result in severe future outbreaks. HeV has caused sporadic infections in horses and a small number of human cases in Australia since 1994. The NiV Malaysia genotype (NiV-M) was responsible for the 1998–1999 epizootic outbreak in pigs with spillover to humans in Malaysia and Singapore. Since 2001, the NiV Bangladesh genotype (NiV-B) has been the predominant strain leading to outbreaks almost every year in Bangladesh and India, with hundreds of infections in humans. The natural reservoir hosts of HeV and NiV are fruit bats, which carry the viruses without clinical manifestation. The transmission pathways of henipaviruses from bats to humans remain poorly understood. Transmissions are often bridged by an intermediate animal host, which amplifies and spreads the viruses to humans. Horses and pigs are known intermediate hosts for the HeV outbreaks in Australia and NiV-M epidemic in Malaysia and Singapore, respectively. During the NiV-B outbreaks in Bangladesh, following initial spillover thought to be through the consumption of date palm sap, the spread of infection was largely human-to-human transmission. Spillover of NiV-B in recent outbreaks in India is less understood, with the primary route of transmission from bat reservoir to the initial human infection case(s) unknown and no intermediate host established. This review aims to provide a concise update on the epidemiology of henipaviruses covering their previous and current outbreaks with emphasis on the known and potential role of livestock as intermediate hosts in disease transmission. Also included is an up-to-date summary of newly emerging henipa-like viruses and animal hosts. In these contexts we discuss knowledge gaps and new challenges in the field and propose potential future directions

Toll-like Interleukin 1 Receptor Regulator Is an Important Modulator of Inflammation Responsive Genes

TILRR (Toll-like interleukin-1 receptor regulator), a transcript variant of FREM1, is a novel regulatory component, which stimulates innate immune responses through binding to IL-1R1 (Interleukin-1 receptor, type 1) and TLR (Toll-like receptor) complex. However, it is not known whether TILRR expression influences other genes in the NFκB signal transduction and pro-inflammatory responses. Our previous study identified FREM1 as a novel candidate gene in HIV-1 resistance/susceptibility in the Pumwani Sex worker cohort. In this study, we investigated the effect of TILRR overexpression on expression of genes in the NFκB signaling pathway in vitro. The effect of TILRR on mRNA expression of 84 genes related to NFκB signal transduction pathway was investigated by qRT-PCR. Overexpression of TILRR on pro-inflammatory cytokine/chemokine(s) secretion in cell culture supernatants was analyzed using Bioplex multiplex bead assay. We found that TILRR overexpression significantly influenced expression of many genes in HeLa and VK2/E6E7 cells. Several cytokine/chemokine(s), including IL-6, IL-8 (CXCL8), IP-10, MCP-1, MIP-1β, and RANTES (CCL5) were significantly increased in the cell culture supernatants following TILRR overexpression. Although how TILRR influences the expression of these genes needs to be further studied, we are the first to show the influence of TILRR on many genes in the NFκB inflammatory pathways. The NFκB inflammatory response pathways are extremely important in microbial infection and pathogenesis, including HIV-1 transmission. Further study of the role of TILRR may identify the novel intervention targets and strategies against HIV infection

High-Level Expression of Notch1 Increased the Risk of Metastasis in T1 Stage Clear Cell Renal Cell Carcinoma

Background: Although metastasis of clear cell renal cell carcinoma (ccRCC) is basically observed in late stage tumors, T1 stage metastasis of ccRCC can also be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signaling in the metastasis of T1 stage ccRCC. Methodology/Principal Findings: The expression of Notch1 and Jagged1 were analyzed in tumor tissues and matched normal adjacent tissues obtained from 51 ccRCC patients. Compared to non-tumor tissues, Notch1 and Jagged1 expression was significantly elevated both in mRNA and protein levels in tumors. Tissue samples of localized and metastatic tumors were divided into three groups based on their tumor stages and the relative mRNA expression of Notch1 and Jagged1 were analyzed. Compared to localized tumors, Notch1 expression was significantly elevated in metastatic tumors in T1 stage while Jagged1 expression was not statistically different between localized and metastatic tumors of all stages. The average size of metastatic tumors was significantly larger than localized tumors in T1 stage ccRCC and the elevated expression of Notch1 was significantly positive correlated with the tumor diameter. The functional significance of Notch signaling was studied by transfection of 786-O, Caki-1 and HKC cell lines with full-length expression plasmids of Notch1 and Jagged1

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO