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Electrically-assisted diffusion bonding (EADB) of a TiBw/TA15 composite with a novel network architecture was studied under a vacuum degree of 3 × 10−3 Pa in this work. Traditional diffusion bonding (TDB) was also investigated to verify the electroplasticity effect. Characterization of the bonding interface revealed that the interface bonding ratio and shear strength increased with bonding time, and the maximum shear strength of the EADB sample could reach 786 MPa when bonded at 4.23 A/mm2 and 2 MPa for 60 min. However, when bonded in the same condition, the EADB sample achieved higher bonding quality than the TDB sample did. Moreover, the potential mechanism through which electropulsing promoted diffusion bonding was studied in detail. The findings provide ideas for EADB of titanium matrix composites.

The ultra-rapid satellite clock product based on the satellite clock batch estimation is commonly used for high-precision and reliable precise point positioning (PPP) services. In order to clarify the effect of different ranging errors on the satellite clock batch estimation accuracy, the source of the satellite clock bias induced by the batch observation model is classified into the initial clock bias (ICB) and time-dependent bias (TDB). In addition to the effect of the ICB and TDB, the analytic relationship between the observation redundancy and the satellite clock batch estimation accuracy are derived and verified. The suitable number of stations is suggested to be 40 for the satellite clock batch estimation to achieve the counterbalance between the efficiency and saturable accuracy. For the PPP based on the batch-estimated satellite clock, the impacts of the ICB and TDB on PPP are clarified. The satellite clock batch estimation and PPP experiments are carried out to investigate the impacts of the ICB and TDB on the satellite clock batch estimation accuracy and the PPP performance. The ICB causes a significant bias for the batch-estimated satellite clock. The TDB is impacted by the assimilation ability of the batch-estimated satellite clock to the satellite orbit error. The convergence time and the positioning accuracy after the convergence of PPP are primarily affected by the ICB and TDB, respectively. [ABSTRACT FROM AUTHOR]

Successful subunit vaccination with recombinant proteins requires adjuvants. The glycolipid trehalose-dibehenate (TDB), a synthetic analog of the mycobacterial cord factor, potently induces Th1 and Th17 immune responses and is a candidate adjuvant for human immunization. TDB binds to the C-type lectin receptor Mincle and triggers Syk-Card9-dependent APC activation. In addition, interleukin (IL)-1 receptor/MyD88-dependent signaling is required for TDB adjuvanticity. The role of different innate immune cell types in adjuvant-stimulated Th1/Th17 responses is not well characterized. We investigated cell recruitment to the site of injection (SOI) and to the draining lymph nodes (dLNs) after immunization with the TDB containing adjuvant CAF01 in a protein-based vaccine. Recruitment of monocytes and neutrophils to the SOI and the dramatic increase in lymph node cellularity was partially dependent on both Mincle and MyD88. Despite their large numbers at the SOI, neutrophils were dispensable for the induction of Th1/Th17 responses. In contrast, CCR2-dependent monocyte recruitment was essential for the induction of Th1/Th17 cells. Transport of adjuvant to the dLN did not require Mincle, MyD88, or CCR2. Together, adjuvanticity conferred by monocytes can be separated at the cellular level from potential tissue damage by neutrophils. [ABSTRACT FROM AUTHOR]

Successful subunit vaccination with recombinant proteins requires adjuvants. The glycolipid trehalose-dibehenate (TDB), a synthetic analog of the mycobacterial cord factor, potently induces Th1 and Th17 immune responses and is a candidate adjuvant for human immunization. TDB binds to the C-type lectin receptor Mincle and triggers Syk-Card9-dependent APC activation. In addition, interleukin (IL)-1 receptor/MyD88-dependent signaling is required for TDB adjuvanticity. The role of different innate immune cell types in adjuvant-stimulated Th1/Th17 responses is not well characterized. We investigated cell recruitment to the site of injection (SOI) and to the draining lymph nodes (dLNs) after immunization with the TDB containing adjuvant CAF01 in a protein-based vaccine. Recruitment of monocytes and neutrophils to the SOI and the dramatic increase in lymph node cellularity was partially dependent on both Mincle and MyD88. Despite their large numbers at the SOI, neutrophils were dispensable for the induction of Th1/Th17 responses. In contrast, CCR2-dependent monocyte recruitment was essential for the induction of Th1/Th17 cells. Transport of adjuvant to the dLN did not require Mincle, MyD88, or CCR2. Together, adjuvanticity conferred by monocytes can be separated at the cellular level from potential tissue damage by neutrophils.

Objective(s): Heparin-binding hemagglutinin (HBHA), a mycobacterial cell surface protein, mediates adhesion to nonphagocytic cells and the dissemination of Mycobacterium tuberculosis (M. tuberculosis) from the site of primary infection. Superior expression systems are required to obtain abundant M. tuberculosis proteins for the purpose of diagnosing M. tuberculosis infection or for the immunization. Here, HBHA was expressed by Pichia pastoris (P. pastoris) GS115 strain , and the immunogenicity of HBHA was evaluated. Materials and Methods: The HBHA gene of M. tuberculosis was cloned into the pPIC9K plasmid, which was good for electroporation into P. pastoris GS115 strain. Unlabeled HBHA protein was purified using a Sepharose CL-6B column, and its expression was confirmed using anti-HBHA polyclonal antibody from mouse serum. We injected C57BL/6 mice with HBHA/ dimethyldioctadecylammonium/trehalose 6,6′-dibehenate (HBHA/DDA/TDB) to investigate the immunogenicity of this potential vaccine. Results: The results demonstrated that HBHA/DDA/TDB has the ability to induce high levels of HBHA-specific IgG antibody and its subclasses, as well as interferon-gamma, compared with injection of phosphate-buffered saline, DDA/TDB alone and Bacillus Calmette-Guérin (BCG) controls (P

Objective(s): Leishmaniasis is a complex parasitic disease that represents a major public health problem. Despite numerous attempts over the past decades, yet there is no effective vaccine against human leishmaniasis probably due to the lack of suitable adjuvants. In this study, a first generation liposomal-based Leishmania vaccine was developed using soluble Leishmania major antigens (SLA) and á, Ü-trehalose6, 6'-dibehenat (TDB) as an immunostimulatory adjuvant. In this liposome structure, the cationic lipid Dimethyldioctadecylammonium (DDA) provides intrinsic adjuvant activity and cholesterol was added as a membrane stabilizer. Liposomes containing SLA were prepared.Materials and Methods: BALB/c mice were subcutaneously (sc) immunized with Lip (DDA/TDB/CHOL)-SLA+, Lip (DDA/TDB)-SLA+, Lip (DDA)-SLA+, Lip (DDA/CHOL)-SLA+, SLA or Tris-HCl buffer. Immunization was done every two weeks for three weeks. The immunized mice were then challenged sc in the left footpad with 1×106 stationary phase L. major promastigotes (50 ìl), at 2 weeks after last booster injection.Results: mice immunized with any of the liposomal formulations containing SLA (Lip-SLA+), substantially increased footpad swelling and parasite loads of foot and spleen with no significant difference compared to Tris-HCl buffer or SLA alone. Lip-SLA+ formulations induced a mixed Th1/Th2 immune response characterized by IFN-ã and IL-4 production as well as high levels of IgG1 anti-Leishmania antibody. Conclusion: immunization with liposomes containing DDA and/or TDB in combination with SLA induces a mixed Th1/Th2 immune response and is not an appropriate strategy for preferential induction of a Th1 response and protection against leishmaniasis.

Both aging and HIV infection are associated with an enhanced pro-inflammatory environment that contributes to impaired immune responses and is mediated in part by innate immune pattern-recognition receptors. MINCLE is a C-type lectin receptor that recognizes trehalose-6,6'-dimycolate or "cord factor," the most abundant glycolipid in Mycobacterium tuberculosis. Here, we evaluated MINCLE function in monocytes in a cohort of HIV-infected and uninfected young (21-35 years) and older adults (≥60 years) via stimulation of peripheral blood mononuclear cells with trehalose-6,6-dibehenate, a synthetic analog of trehalose-6,6'-dimycolate and measurement of cytokine production (interleukin [IL]-10, IL-12, IL-6, tumor necrosis factor-α) by multicolor flow cytometry. Our studies show an age- and HIV-associated increase in cytokine multifunctionality of monocytes both at the population and single cell level that was dominated by IL-12, IL-10, and IL-6. These findings provide insight into the host response to M. tuberculosis and possible sources for the pro-inflammatory environment seen in aging and HIV infection. [ABSTRACT FROM AUTHOR]

Microglial activation has long been recognized as a hallmark of neuroinflammation. Recently, the bacillus Calmette-Guerin (BCG) vaccine has been reported to exert neuroprotective effects against several neurodegenerative disorders. Trehalose-6,6′-dibehenate (TDB) is a synthetic analogue of trehalose-6,6′-dimycolate (TDM, also known as the mycobacterial cord factor) and is a new adjuvant of tuberculosis subunit vaccine currently in clinical trials. Both TDM and TDB can activate macrophages and dendritic cells through binding to C-type lectin receptor Mincle; however, its action mechanism in microglia and their relationship with neuroinflammation are still unknown. In this article, we found that TDB inhibited LPS-induced M1 microglial polarization in primary microglia and BV-2 cells. However, TDB itself had no effects on IKK, p38, and JNK activities or cytokine expression. In contrast, TDB activated ERK1/2 through PLC-γ1/PKC signaling and in turn decreased LPS-induced NF-κB nuclear translocation. Furthermore, TDB-induced AMPK activation via PLC-γ1/calcium/CaMKKβ-dependent pathway and thereby enhanced M2 gene expressions. Interestingly, knocking out Mincle did not alter the anti-inflammatory and M2 polarization effects of TDB in microglia. Conditional media from LPS-stimulated microglial cells can induce in vitro neurotoxicity, and this action was attenuated by TDB. Using a mouse neuroinflammation model, we found that TDB suppressed LPS-induced M1 microglial activation and sickness behavior, but promoted M2 microglial polarization in both WT and Mincle−/− mice. Taken together, our results suggest that TDB can act independently of Mincle to inhibit LPS-induced inflammatory response through PLC-γ1/PKC/ERK signaling and promote microglial polarization towards M2 phenotype via PLC-γ1/calcium/CaMKKβ/AMPK pathway. Thus, TDB may be a promising therapeutic agent for the treatment of neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract The development of the CAF family adjuvant was initiated around 20 years ago when Statens Serum Institut was preparing its first generation protein based recombinant subunit vaccine against tuberculosis for clinical testing, but realized that there were no clinically relevant adjuvants available that would support the strong CMI response needed. Since then the aim for the adjuvant research at Statens Serum Institut has been to provide adjuvants with distinct immunogenicity profiles correlating with protection for any given infectious disease. Two of the adjuvants CAF01 and CAF09 are currently being evaluated in human clinical trials. The purpose of this review is to give an overview of the immunocorrelates of those CAF adjuvants furthest in development. We further aim at giving an overview of the mechanism of action of the CAF adjuvants. [ABSTRACT FROM AUTHOR]

Objective(s): Leishmaniasis is a complex parasitic disease that represents a major public health problem. Despite numerous attempts over the past decades, yet there is no effective vaccine against human leishmaniasis probably due to the lack of suitable adjuvants. In this study, a first generation liposomal-based Leishmania vaccine was developed using soluble Leishmania major antigens (SLA) and á, Ü-trehalose6, 6'-dibehenat (TDB) as an immunostimulatory adjuvant. In this liposome structure, the cationic lipid Dimethyldioctadecylammonium (DDA) provides intrinsic adjuvant activity and cholesterol was added as a membrane stabilizer. Liposomes containing SLA were prepared. Materials and Methods: BALB/c mice were subcutaneously (sc) immunized with Lip (DDA/TDB/CHOL)-SLA+, Lip (DDA/TDB)-SLA+, Lip (DDA)-SLA+, Lip (DDA/CHOL)-SLA+, SLA or Tris-HCl buffer. Immunization was done every two weeks for three weeks. The immunized mice were then challenged sc in the left footpad with 1×106 stationary phase L. major promastigotes (50 ìl), at 2 weeks after last booster injection. Results: mice immunized with any of the liposomal formulations containing SLA (Lip-SLA+), substantially increased footpad swelling and parasite loads of foot and spleen with no significant difference compared to Tris-HCl buffer or SLA alone. Lip-SLA+ formulations induced a mixed Th1/Th2 immune response characterized by IFN-ã and IL-4 production as well as high levels of IgG1 anti-Leishmania antibody. Conclusion: immunization with liposomes containing DDA and/or TDB in combination with SLA induces a mixed Th1/Th2 immune response and is not an appropriate strategy for preferential induction of a Th1 response and protection against leishmaniasis. [ABSTRACT FROM AUTHOR]

In the scope of this work, new carbon dioxide binding organic liquids (CO 2 BOLs) were developed and kinetic parameters in terms of pseudo first-order rate constants for homogenous reaction between CO 2 and CO 2 BOLs in 1-hexanol were obtained by using stopped-flow method with conductivity detection. As an amidine DBN (1,5-diazabicyclo[4.3.0]non-5-ene) and as a guanidine TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) and BTMG (2- tert -butyl-1,1,3,3-tetramethylguanidine) were investigated. Experiments were performed by varying organic base (amidine or guanidine) weight percentage in 1-hexanol medium for a temperature range of 288–308 K. A modified termolecular reaction mechanism was used to analyse the experimental kinetic data. In addition, quantum chemical calculations by using B3LYP, MP2 and CCSD methods were performed to reveal the structural and energetic details of the single step termolecular reaction mechanism. Experimental and theoretical activation energies for these novel carbon dioxide capturing organic liquids were also unveiled. [ABSTRACT FROM AUTHOR]

Abstract: The success of a vaccine consists in the induction of an innate immune response and subsequent activation of the adaptive immune system. Because antigens are usually not immunogenic, the addition of adjuvants that activate innate immunity is required. The mycobacterial cord factor trehalose-6,6′-dimycolate (TDM) and its synthetic adjuvant analogue trehalose-6,6′-dibehenate (TDB) rely on the C-type lectin Mincle and the signaling molecules Syk and Card9 to trigger innate immunity. In this study, we show that stimulation of bone marrow-derived dendritic cells (BMDCs) with TDB induces Nlrp3 inflammasome-dependent IL-1β secretion. While Card9 is required for NF-κB activation by TDB, it is dispensable for TDB-induced activation of the Nlrp3 inflammasome. Additionally, efflux of intracellular potassium, lysosomal rupture, and oxygen radical (ROS) production are crucial for caspase-1 processing and IL-1β secretion by TDB. In an in vivo inflammation model, we demonstrate that the recruitment of neutrophils by TDB is significantly reduced in the Nlrp3-deficient mice compared to the wild-type mice, while the production of chemokines in vitro is not influenced by the absence of Nlrp3. These results identify the Nlrp3 inflammasome as an essential mediator for the induction of an innate immune response triggered by TDB. [Copyright &y& Elsevier]

Abstract: The mechanism behind the immunostimulatory effect of the cationic liposomal vaccine adjuvant dimethyldioctadecylammonium and trehalose 6,6′-dibehenate (DDA:TDB) has been linked to the ability of these cationic vesicles to promote a depot after administration, with the liposomal adjuvant and the antigen both being retained at the injection site. This can be attributed to their cationic nature, since reduction in vesicle size does not influence their distribution profile yet neutral or anionic liposomes have more rapid clearance rates. Therefore the aim of this study was to investigate the impact of a combination of reduced vesicle size and surface pegylation on the biodistribution and adjuvanticity of the formulations, in a bid to further manipulate the pharmacokinetic profiles of these adjuvants. From the biodistribution studies, it was found that with small unilamellar vesicles (SUVs), 10% PEGylation of the formulation could influence liposome retention at the injection site after 4days, whilst higher levels (25mol%) of PEG blocked the formation of a depot and promote clearance to the draining lymph nodes. Interestingly, whilst the use of 10% PEG in the small unilamellar vesicles did not block the formation of a depot at the site of injection, it did result in earlier antibody response rates and switch the type of T cell responses from a Th1 to a Th2 bias suggesting that the presence of PEG in the formulation not only control the biodistribution of the vaccine, but also results in different types of interactions with innate immune cells. [Copyright &y& Elsevier]

Abstract: The adjuvant efficacy of cationic liposomes composed of dimethyldioctadecylammonium bromide and trehalose dibehenate (DDA:TDB) is well established. Whilst the mechanism behind its immunostimulatory action is not fully understood, the ability of the formulation to promote a ‘depot effect’ is a consideration. The depot effect has been suggested to be primarily due to their cationic nature which results in electrostatic adsorption of the antigen and aggregation of the vesicles at the site of injection. The aim of the study was to further test this hypothesis by investigating whether sterically stabilising DDA:TDB with polyethylene glycol (PEG) reduces aggregation, and subsequently influences the formation of a depot at the site of injection. Results reported demonstrate that high (25%) levels of PEG was able to significantly inhibit the formation of a liposome depot and also severely limit the retention of antigen at the site, resulting in a faster drainage of the liposomes from the site of injection. This change in biodistribution profile was reflected in the immunisation response, where lower levels of IgG2b antibody and IFN-γ and higher level of IL-5 cytokine were found. Furthermore entrapping antigen within DDA:TDB liposomes did not improve antigen retention at the injection site compared surface adsorbed antigen. [Copyright &y& Elsevier]

Abstract: Mucosal administration of vaccines has many advantages compared to parenteral vaccination. Needle-free mucosal vaccination would be easily applicable, target the vaccine to the entry point of many pathogens, and reduce the risk of infection with other pathogens during vaccination as compared to invasive methods. CAF01 is a novel liposome-based vaccine adjuvant with remarkable immunostimulatory activity. The potential of CAF01 liposomes as adjuvant for mucosal vaccines was investigated using the Calu-3 epithelial cell culture in vitro model. Thus, the mucosal permeability of the antigen as well as the epithelial integrity and the metabolic activity of the well-differentiated cells were investigated after exposure to CAF01. Finally, the adjuvant was tested for nasal administration in mice, combined with an influenza vaccine. The results suggest that CAF01 enhanced transport of antigen through the mucus layer on Calu-3 cells, increasing the concentration of antigen in the cell layer, as well as the transport across the epithelial cells. Furthermore CAF01 was well tolerated by the Calu-3 cells and the in vivo studies demonstrated increased cell-mediated immunity (CMI) as well as humoral immune responses in mice after nasal application of the influenza vaccine when combined with CAF01. CAF01 is thus a promising adjuvant for mucosal delivery. [Copyright &y& Elsevier]

Abstract: It is of crucial importance to determine the concentration of the different components in the formulation accurately, during production. In this respect, near-infrared (NIR) spectroscopy represents an intriguing alternative that offers rapid, non-invasive and non-destructive sample analysis. This method, combined with multivariate data analysis was successfully applied to quantify the total concentration of lipids in the liposomal CAF01 adjuvant, composed of the cationic surfactant dimethyldioctadecylammonium bromide (DDA) and the immunomodulator α,α′-trehalose 6,6′-dibehenate (TDB). The near-infrared (NIR) detection method was compared to a validated high-performance liquid chromatography (HPLC) method and a differential scanning calorimetry (DSC) analysis, and a blinded study with three different sample concentrations was performed, showing that there was no significant difference in the accuracy of the three methods. However, the NIR and DSC methods were more precise than the HPLC method. Also, with the NIR method it was possible to differentiate between various concentrations of trehalose added as cryo-/lyoprotector. These studies therefore suggest that NIR can be used for real-time process control analysis in the production of CAF01 liposomes. [Copyright &y& Elsevier]

Abstract: Trehalose is a well known protector of biostructures like liposomes and proteins during freeze-drying, but still today there is a big debate regarding its mechanism of action. In previous experiments we have shown that trehalose is able to protect a non-phospholipid-based liposomal adjuvant (designated CAF01) composed of the cationic dimethyldioctadecylammonium (DDA) and trehalose 6,6′-dibehenate (TDB) during freeze-drying [D. Christensen, C. Foged, I. Rosenkrands, H.M. Nielsen, P. Andersen, E.M. Agger, Trehalose preserves DDA/TDB liposomes and their adjuvant effect during freeze-drying, Biochim. Biophys. Acta, Biomembr. 1768 (2007) 2120–2129]. Furthermore it was seen that TDB is required for the stabilizing effect of trehalose. Herein, we show using the Langmuir–Blodgett technique that a high concentration of TDB present at the water-lipid interface results in a surface pressure around 67 mN/m as compared to that of pure DDA which is approximately 47 mN/m in the compressed state. This indicates that the attractive forces between the trehalose head group of TDB and water are greater than those between the quaternary ammonium head group of DDA and water. Furthermore, addition of trehalose to a DDA monolayer containing small amounts of TDB also increases the surface pressure, which is not observed in the absence of TDB. This suggests that even small amounts of trehalose groups on TDB present at the water-lipid interface associate free trehalose to the liposome surface, presumably by hydrogen bonding between the trehalose head groups of TDB and the free trehalose molecules. Hence, for CAF01 the TDB component not only stabilizes the cationic liposomes and enhances the immune response but also facilitates the cryo-/lyoprotection by trehalose through direct interaction with the head group of TDB. Furthermore the results indicate that direct interaction with liposome surfaces is necessary for trehalose to enable protection during freeze-drying. [Copyright &y& Elsevier]

Objective: Gastric cancer is a potential malignant tumor. Extensive research has shown that apoptosis and autophagy are important mechanisms of cancer pathogenesis. This study aimed to explore the role and mechanism of TDB in apoptosis and autophagy in MGC-803 cells., Methods: In cell experiments, the proliferation, apoptosis and autophagy of MGC-803 cells were evaluated by the MTT assay, TUNEL, flow cytometry, MDC, and TEM. Through molecular experiments, the TDB-induced apoptosis and autophagy effects were evaluated by examining the levels of Cleaved-PARP/PARP, Cleaved-caspase3/procaspase3, Beclin-1, p62 and the ratio of LC3-II/LC3-I. At the animal level, the anti-tumor effect of TDB in vivo was evaluated by assessing tumor volume and bioluminescence value., Results: Regarding mechanism, TDB induces apoptosis and autophagy through PI3K/AKT/mTOR. At the same time, more importantly, TDB promotes 3-methyladenine or autophagy activator rapamycin-mediated. The induced proliferation inhibition and pro-apoptosis effect, which inhibit autophagy and induce an increase in apoptosis., Conclusion: TDB may up-regulate PARP, Cleaved Caspase-3, Beclin1 and LC3B and down-regulate the expression of P62 and other apoptosis and autophagy genes through the activation of PI3K/AKT/mTOR pathway signalling proteins, leading to autophagy-dependent apoptosis. At the animal level, TDB has good anti-tumor efficacy in vivo. In summary, TDB has potential anti-tumor efficacy in vivo and in vitro ., Competing Interests: None., (AJTR Copyright © 2021.)

Synthetic mycobacterial cord factor analogues, e.g., trehalose 6,6'-dibehenate (TDB), are highly promising adjuvants due to their strong immunopotentiating capabilities, but their biophysical properties have remained poorly characterized. Here, we report the synthesis of an array of synthetic TDB analogues varying in acyl chain length, degree of acylation, and headgroup display, which was subjected to biophysical characterization of neat nondispersed self-assembled nanostructures in excess buffer and as aqueous dispersions with cationic dimethyldioctadecylammonium (DDA) bromide. The array comprised trehalose mono- (TMX) and diester (TDX) analogues with symmetrically shortened acyl chains [denoted by X: arachidate (A), stearate (S), palmitate (P), myristate (Myr), and laurate (L)] and an analogue with a short hydrophilic polyethylene glycol (PEG) linker inserted between the trehalose headgroup of TDS and the acyl chains (PEG-TDS). All dispersions were liposomes, but in contrast to the colloidally stable and highly cationic TDX-containing liposomes, the zeta-potential was significantly reduced for DDA/TMX and DDA/PEG-TDS liposomes, suggesting a charge-shielding effect, which compromises the colloidal stability. An increased d-spacing was observed for the lamellar phase of neat TDB analogues in excess buffer (TDS < TMS < PEG-TDS), confirming that the charge shielding is caused by an extended molecular configuration of the more flexible headgroup. Differential scanning calorimetry showed highly cooperative phase transitions for all tested dispersions albeit the monoesters destabilized the lipid bilayers. Langmuir experiments demonstrated that incorporation of TDXs and PEG-TDS stabilized DDA monolayers due to improved hydrogen bonding and reduced intermolecular repulsions. In conclusion, data suggest that the DDA/TDS dispersions exhibit favorable physicochemical properties rendering these DDA/TDS liposomes an attractive vaccine adjuvant, and they emphasize that not only the receptor binding and immune activation but also the biophysical properties of immunopotentiator formulations should be collectively considered when designing adjuvants with optimal safety, efficacy, and storage stability.

Advances in technology are the vital factor of competitiveness for technology-intensive companies. Therefore, an intelligent system is required to procure information relevant to technologies. However, the information amount has been dramatically increased. It is no longer possible to analyse the information manually. A methodology to improve the acquisition processes for the identification of technology indicators, which characterise and evaluate technologies, is proposed. This methodology is embedded in the innovative Technology Database developed by Heinz Nixdorf Institute. Decision makers can be well informed about advances in technologies by technology reports and technology roadmaps, which are automatically generated from the database. [ABSTRACT FROM AUTHOR]

Different strategies have been proposed for the development of protein subunit vaccine candidates for tuberculosis (TB), which shows better safety than other types of candidates and the currently used Bacillus Calmette-Guérin (BCG) vaccine. In order to develop more effective protein subunits depending on the mechanism of cell-mediated immunity against TB, a polyprotein CTT3H, based on 5 immunodominant antigens (CFP10, TB10.4, TB8.4, Rv3615c, and HBHA) with CD8(+) epitopes of Mycobacterium tuberculosis, was constructed in this study. We vaccinated C57BL/6 mice with a TB subunit CTT3H protein in an adjuvant of dimethyldioctadecylammonium/monophosphoryl lipid A/trehalose 6,6'-dibehenate (DDA/MPL/TDB, DMT) liposome to investigate the immunogenicity and protective efficacy of this novel vaccine. Our results demonstrated that DMT liposome-adjuvanted CTT3H vaccine not only induced an antigen-specific CD4(+) Th1 response, but also raised the number of PPD- and CTT3H-specific IFN-γ(+) CD8(+) T cells and elicited strong CTL responses against TB10.4, which provided more effective protection against a 60 CFU M. tuberculosis aerosol challenge than PBS control and DMT adjuvant alone. Our findings indicate that DMT-liposome is an effective adjuvant to stimulate CD8(+) T cell responses and the DMT-adjuvanted subunit CTT3H vaccine is a promising candidate for the next generation of TB vaccine.

Current research and development of antigens for vaccination often center on purified recombinant proteins, viral subunits, synthetic oligopeptides or oligosaccharides, most of them suffering from being poorly immunogenic and subject to degradation. Hence, they call for efficient delivery systems and potent immunostimulants, jointly denoted as adjuvants. Particulate delivery systems like emulsions, liposomes, nanoparticles and microspheres may provide protection from degradation and facilitate the co-formulation of both the antigen and the immunostimulant. Synthetic double-stranded (ds) RNA, such as polyriboinosinic acid-polyribocytidylic acid, poly(I:C), is a mimic of viral dsRNA and, as such, a promising immunostimulant candidate for vaccines directed against intracellular pathogens. Poly(I:C) signaling is primarily dependent on Toll-like receptor 3 (TLR3), and on melanoma differentiation-associated gene-5 (MDA-5), and strongly drives cell-mediated immunity and a potent type I interferon response. However, stability and toxicity issues so far prevented the clinical application of dsRNAs as they undergo rapid enzymatic degradation and bear the potential to trigger undue immune stimulation as well as autoimmune disorders. This review addresses these concerns and suggests strategies to improve the safety and efficacy of immunostimulatory dsRNA formulations. The focus is on technological means required to lower the necessary dosage of poly(I:C), to target surface-modified microspheres passively or actively to antigen-presenting cells (APCs), to control their interaction with non-professional phagocytes and to modulate the resulting cytokine secretion profile., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Efforts over the last 2 decades have led to a rich research and development pipeline of tuberculosis (TB) vaccines. Although none of the candidates has successfully completed the clinical trial pipeline, many are under advanced clinical assessment. These vaccines aim at prevention of active TB, with most of them being considered for preexposure with recent additions for postexposure or multistage administration. A few therapeutic vaccines are under clinical assessment, as well. Preexposure vaccination with the licensed TB vaccine BCG prevents severe forms of TB in children but not in adolescents and adults. The current vaccine pipeline does not include strategies which prevent or eliminate infection with the causative agent Mycobacterium tuberculosis (Mtb). Rather in a best-case scenario, they are quantitatively superior to BCG in preventing active TB over prolonged periods of time, ideally lifelong in the face of latent Mtb infection. Qualitatively superior vaccines should be capable of preventing or eliminating Mtb infection, in this way eliminating the risk of TB reactivation. The time is now ripe to exploit radically new strategies to achieve this goal., (Copyright © 2013. Published by Elsevier Ltd.)