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Weibel-type instability can self-generate and amplify magnetic fields in both space and laboratory plasmas with temperature anisotropy. The electron Weibel instability has generally proven more challenging to measure than its ion counterpart owing to the much smaller inertia of electrons, resulting in a faster growth rate and smaller characteristic wavelength. Here, we have probed the evolution of the two-dimensional distribution of the magnetic field components and the current density due to electron Weibel instability, in $\rm CO_2$-ionized hydrogen gas (plasma) with picosecond resolution using a relativistic electron beam. We find that the wavenumber spectra of the magnetic fields are initially broad but eventually shrink to a narrow spectrum representing the dominant quasi-single mode. The measured $k$-resolved growth rates of the instability validate kinetic theory. Concurrently, self-organization of microscopic plasma currents is observed to amplify the current modulation magnitude that converts up to $\sim 1\%$ of the plasma thermal energy into magnetic energy., 24 pages, 4 figures

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are characterized by the aberrant accumulation of intracytoplasmic misfolded and aggregated α-synuclein (α-Syn), resulting in neurodegeneration associated with inflammation. The propagation of α-Syn aggregates from cell to cell is implicated in the spreading of pathological α-Syn in the brain and disease progression. We and others demonstrated that antibodies generated after active and passive vaccinations could inhibit the propagation of pathological α-Syn in the extracellular space and prevent/inhibit disease/s in the relevant animal models. We recently tested the immunogenicity and efficacy of four DNA vaccines on the basis of the universal MultiTEP platform technology in the DLB/PD mouse model. The antibodies generated by these vaccines efficiently reduced/inhibited the accumulation of pathological α-Syn in the different brain regions and improved the motor deficit of immunized female mice. The most immunogenic and preclinically effective vaccine, PV-1950D, targeting three B-cell epitopes of pathological α-Syn simultaneously, has been selected for future IND-enabling studies. However, to ensure therapeutically potent concentrations of α-Syn antibodies in the periphery of the vaccinated elderly, we developed a recombinant protein-based MultiTEP vaccine, PV-1950R/A, and tested its immunogenicity in young and aged D-line mice. Antibody responses induced by immunizations with the PV-1950R/A vaccine and its homologous DNA counterpart, PV-1950D, in a mouse model of PD/DLB have been compared.

Substituting the solid piston of conventional reciprocating compressors used for the compression of hydrogen with a suitable ionic liquid will solve many practical problems and limitations that conventional reciprocating compressors face. However, because of the large number of cation and anion combinations and many studies on the unique properties of ionic liquids and the role of ionic liquid cations and anions in determining these properties, a systematic review is required to narrow down the choice of ionic liquids. Therefore, in the present review, a comprehensive study to find the most appropriate ionic liquid candidate to replace the solid piston in reciprocating compressors for compressing hydrogen is reported. Specific criteria concerning the applications of ionic liquids are determined and the roles of the cations and anions, as well as the effect of temperature, are extensively reviewed to identify the most suitable ionic liquid that can fulfill the requirements. As a next step, the options are narrowed down to five ionic liquids with the triflate and bis(trifluoromethylsulfonyl)imide as the anion choices and three different cation types, imidazolium-, phosphonium-, and ammonium-based, as the cation choices. Finally, the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide is recommended as the best candidate that can be safely used as a replacement for the solid piston in reciprocating compressors for compressing hydrogen in hydrogen stations.

The advent of chirped-pulse amplification in the 1980s and femtosecond Ti:sapphire lasers in the 1990s enabled transformative advances in intense laser–matter interaction physics. Whereas most of experiments have been conducted in the limited near-infrared range of 0.8–1 μm, theories predict that many physical phenomena such as high harmonic generation in gases favor long laser wavelengths in terms of extending the high-energy cutoff. Significant progress has been made in developing few-cycle, carrier-envelope phase-stabilized, high-peak-power lasers in the 1.6–2 μm range that has laid the foundation for attosecond X ray sources in the water window. Even longer wavelength lasers are becoming available that are suitable to study light filamentation, high harmonic generation, and laser–plasma interaction in the relativistic regime. Long-wavelength lasers are suitable for sub-bandgap strong-field excitation of a wide range of solid materials, including semiconductors. In the strong-field limit, bulk crystals also produce high-order harmonics. In this review, we first introduce several important wavelength scaling laws in strong-field physics, then describe recent breakthroughs in short- (1.4–3 μm), mid- (3–8 μm), and long-wave (8–15 μm) infrared laser technology, and finally provide examples of strong-field applications of these novel lasers. Some of the broadband ultrafast infrared lasers will have profound effects on medicine, environmental protection, and national defense, because their wavelengths cover the water absorption band, the molecular fingerprint region, as well as the atmospheric infrared transparent window.

Generation and amplification of magnetic fields in plasmas is a long-standing topic that is of great interest to both plasma and space physics. The electron Weibel instability is a well-known mechanism responsible for self-generating magnetic fields in plasmas with temperature anisotropy and has been extensively investigated in both theory and simulations, yet experimental verification of this instability has been challenging. Recently, we demonstrated a new experimental platform that enables the controlled initialization of highly nonthermal and/or anisotropic plasma electron velocity distributions via optical-field ionization. Using an external electron probe bunch from a linear accelerator, the onset, saturation and decay of the self-generated magnetic fields due to electron Weibel instability were measured for the first time to our knowledge. In this paper, we will first present experimental results on time-resolved measurements of the Weibel magnetic fields in non-relativistic plasmas produced by Ti:Sapphire laser pulses (0.8 $\mu m$) and then discuss the feasibility of extending the study to quasi-relativistic regime by using intense $\rm CO_2$ (e.g., 9.2 $\mu m$) lasers to produce much hotter plasmas., Comment: 22 pages, 10 figures

Solenoids are frequently used for focusing low-energy beams. In this paper, we show how they can serve as multipurpose diagnostics tools to measure various beam parameters, including energy, emittance, the second moments of the transverse distribution, and the beam position and angle with respect to the solenoid’s axis. The energy measurement is based on rotation of the plane of the transverse motion, as opposed to generating dispersion with a dipole. Measurement of the beam trajectory with respect to the solenoid axis is done by analyzing the beam orbit downstream of the solenoid while varying its current. The second moments are calculated by analyzing the beam image on a profile monitor while accounting for the beam rotation caused by the solenoid. We describe in detail the corresponding procedures and the experimental results of these measurements.

High brightness, high charge electron beams are critical for a number of advanced accelerator applications. The initial emittance of the electron beam, which is determined by the mean transverse energy (MTE) and laser spot size, is one of the most important parameters determining the beam quality. The bialkali photocathodes illuminated by a visible laser have the advantages of high quantum efficiency (QE) and low MTE. Furthermore, Superconducting Radio Frequency (SRF) guns can operate in the continuous wave (CW) mode at high accelerating gradients, e.g. with significant reduction of the laser spot size at the photocathode. Combining the bialkali photocathode with the SRF gun enables generation of high charge, high brightness, and possibly high average current electron beams. However, integrating the high QE semiconductor photocathode into the SRF guns has been challenging. In this article, we report on the development of bialkali photocathodes for successful operation in the SRF gun with months-long lifetime while delivering CW beams with nano-coulomb charge per bunch. This achievement opens a new era for high charge, high brightness CW electron beams.

Continuous-wave photoinjectors operating at high accelerating gradients promise to revolutionize many areas of science and applications. They can establish the basis for a new generation of monochromatic x-ray free electron lasers, high-brightness hadron beams, or a new generation of microchip production. In this Letter we report on the record-performing superconducting rf electron gun with CsK_{2}Sb photocathode. The gun is generating high charge electron bunches (up to 10 nC/bunch) and low transverse emittances, while operating for months with a single photocathode. This achievement opens a new era in generating high-power beams with a very high average brightness.

Cyclic voltammetry was performed with a nickel electrode in molten CsH2PO4 at 350 °C and at approximately 25 bar of water pressure. The effect of adding carbon dioxide was examined. It is found that even small amounts of CO2 (partial pressure below 0.2 bar at 350 °C, corresponding to 0.5 bar at 22 °C of a 5:1 mixture of N2:CO2) have a pronounced effect on the cyclic voltammetry curves. Under these conditions the hydrogen formation is substituted by another process, methane formation. At the same time the cathodic current increased by a factor of 4–6, meaning that the ease of methanisation was much improved.

Pathological tau correlates well with cognitive impairments in Alzheimer’s disease (AD) patients and therefore represents a promising target for immunotherapy. Targeting an appropriate B cell epitope in pathological tau could in theory produce an effective reduction of pathology without disrupting the function of normal native tau. Recent data demonstrate that the N-terminal region of tau (aa 2-18), termed the “phosphatase activation domain (PAD)”, is hidden within native Tau in a ‘paperclip’-like conformation. Conversely, PAD is exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and tau polymerization. Thus, we hypothesized that anti-tau2-18 antibodies may safely and specifically reduce pathological tau and prevent further aggregation, which in turn would neutralize tau toxicity. Therefore, we evaluated the immunogenicity and therapeutic efficacy of our MultiTEP platform-based vaccine targeting tau2-18 formulated with AdvaxCpG adjuvant (AV-1980R/A) in PS19 tau transgenic mice. The AV-1980R/A induced extremely high antibody responses and the resulting sera recognized neurofibrillary tangles and plaque-associated dystrophic neurites in AD brain sections. In addition, under non-denaturing conditions AV-1980R/A sera preferentially recognized AD-associated tau. Importantly, vaccination also prevented age-related motor and cognitive deficits in PS19 mice and significantly reduced insoluble total and phosphorylated tau species. Taken together, these findings suggest that predominantly targeting misfolded tau with AV-1980R/A could represent an effective strategy for AD immunotherapy.

Previously, we reported that Alzheimer's disease (AD) epitope vaccines (EVs) composed of N-terminal β-amyloid (Aβ 42 ) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Aβ 42 is a target. Here, we directly compare the efficacy of anti-Aβ 42 antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6–6.5 months for preventive vaccinations and 16–19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Aβ antibodies, significantly reducing pathologic forms of Aβ in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11–11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Aβ antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance.

A new potentially high-efficiency electrolyte for water electrolysis: molten monobasic potassium phosphate, KH2PO4 or KDP has been investigated at temperatures ∼275–325 °C. At these temperatures, KH2PO4 was found to dissociate into H2O gas in equilibrium with a melt mixture of KH2PO4—K2H2P2O7—KPO3—H2O. The water vapor pressure above the melt, when contained in a closed ampoule, was determined quantitatively vs. temperature by use of Raman spectroscopy with methane or hydrogen gas as an internal calibration standard, using newly established relative ratios of Raman scattering cross sections of water and methane or hydrogen to be 0.40 ± 0.02 or 1.2 ± 0.03. At equilibrium the vapor pressure was much lower than the vapor pressure above liquid water at the same temperature. Electrolysis was realized by passing current through closed ampoules (vacuum sealed quartz glass electrolysis cells with platinum electrodes and the electrolyte melt). The formation of mixtures of hydrogen and oxygen gases as well as the water vapor was detected by Raman spectroscopy. In this way it was demonstrated that water is present in the new electrolyte: molten KH2PO4 can be split by electrolysis via the reaction 2H2O → 2H2 + O2 at temperatures ∼275–325 °C. At these temperatures, before the start of the electrolysis, the KH2PO4 melt gives off H2O gas that pressurizes the cell according to the following dissociations: 2KH2PO4 ↔ K2H2P2O7 + H2O ↔ 2KPO3 + 2H2O. The spectra show however that the water by virtue of hydrogen-bonding has a high affinity for remaining in the melt. The formed hydrogen and oxygen gasses were detected by means of the characteristic Raman gas-phase spectra.

The corrosion behavior of various commercially available stainless steels and nickel-based alloys as possible construction materials for components which are in direct contact with one of five different ionic liquids was evaluated. The ionic liquids, namely: 1-ethyl-3-methylimidazolium triflate, 1-ethyl-3-methylimidazolium bis (trifluoromethylsulfonyl) imide, trihexyltetradecylphosphonium bis (trifluoromethylsulfonyl) imide, butyltrimethylammonium bis (trifluoromethylsulfonyl) imide, methyltrioctylammonium bis (trifluoromethylsulfonyl) imide have been identified, as performance fluids in an ionic liquid hydrogen compressor. An electrochemical cell was specially designed, and steady-state cyclic voltammetry was used to measure the corrosion resistance of the alloys in the ionic liquids at 23 °C, under atmospheric pressure. The results showed a very high corrosion resistance and high stability for all the alloys tested. The two stainless steels, AISI 316L and AISI 347 showed higher corrosion resistance compared to AISI 321 in all the ionic liquids tested. It was observed that small addition of molybdenum, tantalum, and niobium to the alloys increased the corrosion stability in the ionic liquids studied. Hastelloy® C-276 showed the poorest corrosion resistance in all the ionic liquids tested. AISI 316L with high corrosion resistance and the lowest cost is recommended as the most attractive construction material for all the components, in an ionic liquid hydrogen compressor, which are in direct contact with ionic liquids used in this study.

The conductivity of pure molten KH2PO4 salt and four mixtures with more or less water (KH2PO4-H2O and KH2PO4-KPO3 systems, respectively) were measured at temperatures of 240-320°C and under their own water vapor pressures. Molten KH2PO4 has been proven to be a promising electrolyte for an elevated temperature pressurized water electrolyzer demonstrating high conductivity of ∼0.30Scm-1 at 300°C. The conductivity data are given as polynomial functions of temperature and composition. The melting point of the pure salt under its own water vapor pressure was determined to be ∼272°C.

Long wavelength infrared laser-driven plasma wakefield accelerators are investigated here in the self-modulated laser wakefield acceleration (SM-LWFA) and blowout regimes using 3D particle-in-cell simulations. The simulation results show that in the SM-LWFA regime, self-injection arises with wave breaking, whereas in the blowout regime, self-injection is not observed under the simulation conditions. The wave breaking process in the SM-LWFA regime occurs at a field strength that is significantly below the 1D wave-breaking threshold. This process intensifies at higher laser power and plasma density and is suppressed at low plasma densities ( ≤ 1 × 10 17 cm − 3 here). The produced electrons show spatial modulations with a period matching that of the laser wavelength, which is a clear signature of direct laser acceleration.

It has been shown that methane can be formed in high amounts by co-electrolysis of CO2 and H2O using a nickel cathode, a CsH2PO4–SiC composite electrolyte and an IrO2 anode. The experimental conditions were 300 °C and 8 bar. The maximum efficiency close to 100% for methane was obtained at a current density of 10–15 mA cm−2. A small amount of hydrogen was formed as the only other product.

The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aβ peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aβ pathology in a pre-clinical translational study. Biodistribution studies two days after the injection demonstrated high copy numbers of AV-1959D plasmid after single immunization of Tg2576 mice at the injection sites but not in the tissues of distant organs. Plasmids persisted at the injection sites of some mice 60 days after vaccination. In Tg2576 mice with established amyloid pathology, we did not observe short- or long-term toxicities after multiple immunizations with three doses of AV-1959D. Assessment of the repeated dose acute safety of AV-1959D in cerebral amyloid angiopathy (CAA) prone Tg-SwDI mice did not reveal any immunotherapy-induced vasogenic edema detected by magnetic resonance imaging (MRI) or increased microhemorrhages. Multiple immunizations of Tg-SwDI mice with AV-1959D did not induce T and B cell infiltration, glial activation, vascular deposition of Aβ, or neuronal degeneration (necrosis and apoptosis) greater than that in the control group determined by immunohistochemistry of brain tissues. Taken together, the safety data from two different mouse models of AD substantiate a favorable safety profile of the cGMP grade AV-1959D vaccine supporting its progression to first-in-human clinical trials.

Superconducting rf (SRF) photoinjectors are one of the most promising devices for generating continuous wave (CW) electron beams with record high brightness. Ultrahigh vacuum of SRF guns provides for long lifetime of the high quantum efficiency (QE) photocathodes, while SRF technology provides for high accelerating gradients exceeding $10\text{ }\text{ }\mathrm{MV}/\mathrm{m}$. It is especially true for low frequency SRF guns where electrons are generated at photocathodes at the crest of accelerating voltage. Two main physics challenges of SRF guns are their compatibility with high QE photocathodes and multipacting. The first is related to a possibility of deposition of photocathode materials (such as Cs) on the walls of the SRF cavity, which can result in increased dark current via reduction of the bulk Nb work function and in enhancing of a secondary electron emission yield (SEY). SEY plays critical role in multipacting (e.g., an exponential growth of the multipactor discharge), which could both spoil the gun vacuum and speed up the deposition of the cathode material on the walls of the SRF cavity. In short, the multipactor behavior in superconducting accelerating units must be well understood for successful operation of an SRF photo-injector. In this paper we present our studies of 1.2 MV 113 MHz quarter-wave SRF photoinjector serving as a source of electron beam for the coherent electron cooling experiment (CeC) at BNL. During three years of operating our SRF gun we encountered a number of multipacting zones. We also observed that presence of ${\mathrm{CsK}}_{2}\mathrm{Sb}$ photocathode in the gun could create additional multipacting barriers. We had conducted a comprehensive numerical and experimental study of the multipactor discharge in our SRF gun. We had developed a process of crossing the multipacting barriers from zero to the operational voltage without affecting the lifetime of our photocathode and enhancing the strength of multipacting barriers. We found a good agreement between the results of simulations and our experimental data.

One limitation for large scale water electrolysis is the high price of the Pt cathode catalyst. Transition metal carbides, which are considered as some of the most promising non-Pt catalysts, are less active than Pt at room temperature. The present work demonstrates that the situation is different at medium temperatures (200–400 °C). By introducing a new setup which makes use of molten KH2PO4 as electrolyte, a model system for solid acid membrane electrolyser cells was obtained. Metal carbide coated wires prepared by a two-step oxidation–carburization reaction of the metal wire surfaces were used as electrodes and allowed the measurement of the intrinsic catalytic properties of different transition metal carbides in direct comparison to Pt at 260 °C. Under these conditions, the activity in the hydrogen evolution reaction (HER) followed the order WC > Pt ≈ Mo2C > NbC > TaC.

DNA vaccines promote immune system activation in small animals and exhibit certain advantages when compared to conventional recombinant protein vaccines. However in clinical trials DNA vaccines are less effective in inducing potent immune responses due to the low delivery efficiency and expression of antigens. Currently, various delivery devices such as gene-guns, bioinjectors and electroporation systems are being used in order to increase the potency of DNA vaccines. However, the optimal delivery parameters are required and must be carefully set to obtain the highest levels of gene expression and strong immune responses in humans. The focus of this study was to optimize electroporation settings (voltage, pulse length, pulse intervals, and number of pulses), as well as the route of administration (intradermal vs. intramuscular) and dosage of the DNA epitope vaccine, AV-1959D, delivered by the BTX AgilePulse(TM) system. As a result, we have chosen the optimal settings for electroporation delivery using different routes of immunization with this vaccine, generating (i) robust antibody production to the B cell epitope (a small peptide, derived from β-amyloid), and (ii) strong cellular immune responses to Th epitopes (a small synthetic peptide and eleven peptides from various pathogens) incorporated into DNA vaccine platform.

Immunotherapeutic approaches to treating Alzheimer's disease (AD) using vaccination strategies must overcome the obstacle of achieving adequate responses to vaccination in the elderly. Here we demonstrate for the first time that application of the Escherichia coli heat-labile enterotoxin adjuvant-laden immunostimulatory patches (LT-IS) dramatically enhances the onset and magnitude of immune responses to DNA- and protein-based vaccines for Alzheimer's disease following intradermal immunization via gene gun and conventional needles, respectively. Our studies suggest that the immune activation mediated by LT-IS offers improved potency for generating AD-specific vaccination responses that should be investigated as an adjuvant in the clinical arena.

Background As a prelude to clinical trials we have characterized B- and T-cell immune responses in macaques to AD vaccine candidates: AV-1955 and its slightly modified version, AV-1959 (with 3 additional promiscuous Th epitopes). Methods T- and B-cell epitope mapping was performed using the ELISPOT assay and competition ELISA, respectively. Results AV-1955 and AV-1959 did not stimulate potentially harmful autoreactive T cells, but instead activated a broad but individualized repertoire of Th cells specific to the MultiTEP platform in macaques. Although both vaccines induced robust anti-Aβ antibody responses without producing antibodies specific to Th epitopes of MultiTEP platforms, analyses of cellular immune responses in macaques demonstrated that the addition of Th epitopes in the case of AV-1959 created a more potent, superior vaccine. Conclusion AV-1959 is a promising vaccine candidate capable of producing therapeutically potent anti-amyloid antibody in a broader population of vaccinated subjects with high MHC class II gene polymorphisms.

Immunotherapeutic approaches reducing α-synuclein deposits may provide therapeutic benefit for Dementia with Lewy Bodies (DLB). Immunization with full-length human α-synuclein (hα-Syn) protein in a Parkinson's disease mouse model decreased the accumulation of the aggregated forms of this protein in neurons and reduced neurodegeneration. To enhance the immunogenicity of candidate vaccines and to avoid the risk of autoreactive anti-hα-Syn T-helper (Th) cell responses, we generated three peptide-based epitope vaccines composed of different B-cell epitopes of hα-Syn fused with a "non-self" Th epitope from tetanus toxin (P30). Immunization of mice with these epitope vaccines produced high titers of anti-hα-Syn antibodies that bound to Lewy bodies (LBs) and Lewy neurites (LNs) in brain tissue from DLB cases and induced robust Th cell responses to P30, but not to hα-Syn. Further development of these first generation epitope vaccines may facilitate induction of anti-hα-Syn immunotherapy without producing potentially harmful autoreactive Th cell responses.

Background Clinical trials with passive and active Alzheimer's disease (AD) vaccines suggest that early interventions are needed for improvement of cognitive and/or functional performance in patients, providing impetus for the development of safe and immunologically potent active vaccines targeting amyloid β (Aβ). The AN-1792 trial has indicated that Aβ-specific T cells may be unsafe for humans; therefore, other vaccines based on small Aβ epitopes are undergoing preclinical and clinical testing. Methods Humoral and cellular immune responses elicited in response to a novel DNA epitope-based vaccine (AV-1955) delivered to rhesus macaques using the TriGrid electroporation device were evaluated. Functional activities of anti-Aβ antibodies generated in response to vaccination were assessed in vitro . Results AV-1955 generates long-term, potent anti-Aβ antibodies and cellular immune responses specific to foreign T-helper epitopes but not to self-Aβ. Conclusions This translational study demonstrates that a DNA-based epitope vaccine for AD could be appropriate for human clinical testing.

We have previously demonstrated that anti-beta amyloid DNA vaccine (AV-1959D) based on our proprietary MultiTEP platform technology is extremely immunogenic in mice, rabbits, and monkeys. Importantly, MultiTEP platform enables development of vaccines targeting pathological molecules involved in various neurodegenerative disorders. Taking advantage of the universality of MultiTEP platform, we developed DNA vaccines targeting 3 B-cell epitopes (amino acids [aa]85-99, aa109-126, and aa126-140) of human alpha-synuclein (hα-Syn) separately or all 3 epitopes simultaneously. All 4 DNA vaccines (1) generate high titers of anti-hα-Syn antibodies and (2) induce robust MultiTEP-specific T-helper cell responses without activation of potentially detrimental autoreactive anti-hα-Syn T-helper cells. Generated antibodies recognize misfolded hα-Syn produced by neuroblastoma cells, hα-Syn in the brain tissues of transgenic mouse strains and in the brain tissues of dementia with Lewy body cases. Based on these results, the most promising vaccine targeting 3 B-cell epitopes of hα-Syn simultaneously (PV-1950D) has been chosen for ongoing preclinical assessment in mouse models of hα-Syn with the aim to translate it to the human clinical trials.

Background The experience from clinical trials indicates that anti-Aβ immunotherapy could be effective in early/pre-clinical stages of AD, whereas at the late stages promoting the clearing of Aβ alone may be insufficient to halt the disease progression. At the same time, pathological tau correlates much better with the degree of dementia than Aβ deposition. Therefore, targeting pathological tau may provide a more promising approach for the treatment of advanced stages of AD. Recent data demonstrates that the N-terminal region of tau spanning aa 2–18 termed “phosphatase activation domain” that is normally hidden in the native protein in ‘paperclip’-like conformation, becomes exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and in aggregation of tau. Hence, we hypothesized that anti-Tau2–18 monoclonal antibodies (mAb) may recognize pathological, but not normal tau at very early stages of tauopathy and prevent or decrease the aggregation of this molecule. Methods Mouse mAbs were generated using standard hybridoma methodology. CDR grafting was used for humanization of mouse mAb. Humanized mAb (Armanezumab) was characterized and tested in vitro/ex vivo/in vivo using biochemical and immunological methods (HPLC, Biacore, ELISA, IHC, FRET, etc.). Stable DG44 cell line expressing Armanezumab was generated by clone selection with increased concentrations of methotrexate (MTX). Results A panel of mouse mAbs was generated, clone 1C9 was selected based on binding to pathological human tau with high affinity and humanized. Fine epitope mapping revealed conservation of the epitope of human tau recognized by the parent murine mAb and Armanezumab. Importantly, Armanezumab (i) bound to tau with high affinity as determined by Biacore; (ii) bound pathological tau in brains from AD, FTD and Pick’s disease cases; (iii) inhibited seeding effect of aggregated tau from brain lysate of P301S Tg mice; (iv) inhibited cytotoxic effect of tau oligomers; (v) reduced total tau (HT7) and AT100, PHF1, AT8, AT180, p212, p214-positive tau species in brains of tau transgenic mice after intracranial injection. A stable CHO cell line producing >1.5 g/l humanized mAb, Armanezumab was generated. Conclusion These findings suggest that Armanezumab could be therapeutic in clinical studies for treatment of AD.

Background: By the time clinical symptoms of Alzheimer’s disease (AD) manifest in patients there is already substantial tau pathology in the brain. Recent evidence also suggests that tau pathology can become self-propagating, further accelerating disease progression. Over the last decade several groups have tested the efficacy of protein-based anti-tau immunotherapeutics in various animal models of tauopathy. Here we report on the immunological and therapeutic potency of the first anti-tau DNA vaccine based on the MultiTEP platform, AV-1980D, in THY-Tau22 transgenic mice. Methods: Starting at 3 months of age, mice were immunized intramuscularly with AV-1980D vaccine targeting a tau B cell epitope spanning aa2-18 followed by electroporation (EP). Humoral and cellular immune responses in vaccinated animals were analyzed by ELISA and ELISpot, respectively. Neuropathological changes in the brains of experimental and control mice were then analyzed by biochemical (WB and ELISA) and immunohistochemical (IHC) methods at 9 months of age. Results: EP-mediated AV-1980D vaccinations of THY-Tau22 mice induced activation of Th cells specific to the MultiTEP vaccine platform and triggered robust humoral immunity response specific to tau. Importantly, no activation of potentially harmful autoreactive Th cell responses specific to endogenous tau species was detected. The maximum titers of anti-tau antibodies were reached after two immunizations and remained slightly lower, but steady during five subsequent monthly immunizations. Vaccinations with AV-1980D followed by EP significantly reduced total tau and pS199 and AT180 phosphorylated tau levels in the brains extracts of vaccinated mice, but produced on subtle non-significant effects on other phosphorylated tau species. Conclusions: These data demonstrate that MultiTEP-based DNA epitope vaccination targeting the N-terminus of tau is highly immunogenic and therapeutically potent in the THY-Tau22 mouse model of tauopathy and indicate that EP-mediated DNA immunization is an attractive alternative to protein-based adjuvanted vaccines for inducing high concentrations of anti-tau antibodies.

Stainless steels (AISI 316, 321 and 347), high-nickel alloys (Hasteloy®C-276 and Inconel®625), tantalum, nickel, titanium, tungsten, molybdenum, niobium, platinum, and gold were tested for corrosion resistance in molten KH2PO4 (or KH2PO4-K2H2P2O7) as a promising electrolyte for the intermediate-temperature (200–400°C) water electrolysis. Pt, Ta, Nb, Ti, Inconel®625, and Ni demonstrated high corrosion resistance. Au and the rest of the tested materials were not corrosion resistant. It means that Ni, Ti and Inconel®625 may be used as relatively cheap construction materials for the intermediate-temperature water electrolyzer.

Although β-amyloid (Aβ) may be the primary driver of Alzheimer’s disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aβ and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aβ (AV-1959R), Tau (AV-1980R) or Aβ/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with AdvaxCpG, delta inulin, Alhydrogel®, Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in AdvaxCpG induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with AdvaxCpG induced robust antibody responses against various forms of both, Aβ and tau pathological molecules. While anti-Aβ antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials.

Tungsten carbide (WC) nanopowder was tested as a non-platinum cathode electrocatalyst for polymer electrolyte membrane (PEM) water electrolysers, operating at elevated temperatures. It was prepared in thermal plasma reactor with confined plasma jet from WO3 precursor in combination with CH4 carburizing agent. The results of the investigation showed that the activity of tungsten carbide as cathode electrocatalyst increases significantly with temperature and this effect is more pronounced than for platinum, especially, at 150 °C.

Commercial TaC and Si3N4 powders were tested as possible electrocatalyst support materials for the Oxygen Evolution Reaction (OER) for PEM water electrolysers, operating at elevated temperatures. TaC and Si3N4 were characterised by thermogravimmetric and differential thermal analysis for their thermal stability. The Adams fusion method was implemented to deposit IrO2 on the support surfaces. A series of electrocatalysts was prepared with a composition of (IrO2)x(TaC/ Si3N4)1-x,where x represents the mass fraction of IrO2 and was equal to 0.1 (only for TaC), 0.3, 0.5, 0.7, 0.9 and 1. The thin-film method was used for electrochemical analysis of the prepared electrocatalysts. SEM-EDX, BET and powder conductivity measurements were used as complementary techniques to complete characterisation of the electrocatalysts. Additionally, they were compared in their properties with previously reported data for a SiC-Si support. The stability of the electrocatalysts was assessed by estimation of reversibility of the anodic/cathodic processes.

Iridium oxide (IrO 2 ) currently represents a state of the art electrocatalyst for anodic oxygen evolution. Since iridium is both expensive and scarce, the future practical application of this process makes it essential to reduce IrO 2 loading on the anodes of PEM water electrolysers. In the present study an approach to utilising a suitable electrocatalyst support was followed. Of the materials selected from a literature review, TaC has proved to be stable under the conditions of the accelerated stability test proposed in this study. The test involved dispersing each potential support material in a mixture of trifluoromethanesulfonic acid (TFMSA) and hydrogen peroxide at 130 °C. The liquid phase was subsequently analysed using ICP-MS with respect to the occurrence of ions potentially originating from the support material tested. The TaC support selected was additionally characterised by thermogravimmetric and differential thermal analysis to prove its thermal stability. A modified version of the Adams fusion method was used to deposit IrO 2 on the support surface. A series of electrocatalysts was prepared with a composition of (IrO 2 ) x (TaC) 1− x , where x represents the mass fraction of IrO 2 and was equal to 0.1, 0.3, 0.5, 0.7, 0.9 and 1. The thin-film method was used for electrochemical characterisation of the electrocatalysts prepared. SEM–EDX analysis, X-ray diffraction, N 2 adsorption (BET) and powder conductivity measurements were used as complementary techniques to complete characterisation of the electrocatalysts prepared. The electrocatalysts with x ≥ 0.5 showed stable specific activity. This result is consistent with the conductivity measurements.

Background: Induction of a humoral response against amyloid-β peptide may be beneficial for Alzheimer’s disease (AD) patients and may alleviate the onset and progression of AD. DNA-based vaccination provides a unique alternative method of immunization for treatment and prevention of AD. Currently, the two major delivery methods used for enhancing DNA uptake and immune responses to DNA vaccines in humans are electroporation (EP) and gene gun (GG). Objective: The goal of this translational study was to evaluate the efficacy of an AD DNA epitope vaccine (DepVac) delivered intramuscularly by EP or intradermally by GG. Methods: Humoral and cellular immune responses to immunization with DepVac were evaluated by ELISA and ELISPOT, respectively. Functional activity of the antibodies was also assessed. Results: EP- and GG-mediated immunizations with DepVac induced similar anti-amyloid-β (Aβ) antibody and T cell responses. Anti-Aβ antibodies bound to amyloid plaques in AD brain tissue and to toxic forms of Aβ42 peptide. Conclusion: Both delivery methods are effective at promoting potent antibodies specific for Aβ.

A novel catalyst material for oxygen evolution electrodes was prepared and characterised by different techniques. IrO 2 supported on a SiC–Si composite was synthesised by the Adams fusion method. XRD and nitrogen adsorption experiments showed an influence of the support on the surface properties of the IrO 2 particles, affecting the IrO 2 particle size. The prepared catalysts were electrochemically characterised by cyclic voltammetry experiments at 25,80,120 and 150 °C. In accordance with the observed variation in particle size, a support loading of up to 20% improved the activity of the catalyst. Powder conductivity measurements were also performed, which showed the influence of the support particles in the packing of IrO 2 particles, perhaps favouring the formation of channels and pores between particles, thus increasing the catalyst utilisation.

Different types of commercially available stainless steels, Ni-based alloys as well as titanium and tantalum were evaluated as possible metallic bipolar plates and construction materials. The corrosion resistance was measured under simulated conditions corresponding to the conditions in high temperature proton exchange membrane (PEM) steam electrolysers. Steady-state voltammetry was used in combination with scanning electron microscopy and energy-dispersive X-ray spectroscopy to evaluate the stability of the mentioned materials. It was found that stainless steels were the least resistant to corrosion under strong anodic polarisation. Among alloys, Ni-based showed the highest corrosion resistance in the simulated PEM electrolyser medium. In particular, Inconel® 625 was the most promising among the tested corrosion-resistant alloys for the anodic compartment in high temperature steam electrolysis. Tantalum showed outstanding resistance to corrosion in selected media. On the contrary, passivation of titanium was weak, and the highest rate of corrosion among all tested materials was observed for titanium at 120 °C.