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Highly pathogenic avian influenza viruses from H5 clade 2.3.4.4b are circulating at unprecedently high levels in wild and domestic birds and have the potential to adapt to humans. We generated an mRNA lipid nanoparticle (LNP) vaccine encoding the hemagglutinin (HA) glycoprotein from a clade 2.3.4.4b H5 isolate. We show that the vaccine is immunogenic in mice and ferrets and prevents morbidity and mortality of ferrets following 2.3.4.4b H5N1 challenge.

Background Global demand for cocoa butter (CB) product is rising, but the production of CB does not meet the demand, and the availability of this fat is also limited. CB has specific melting properties, and the blooming effect causes defect in its physical properties. The blending of fat is one of the modification methods that offer new functional CB alternatives (CBAs) that can enhance the properties of CB and be applied as substitutes in the food industry. Scope and approach This review describes the current trends in blending the pure or modified vegetable fats and oils for CBAs production and summarises the characteristics of the blended substances. Typical and recent fats and oils used for CBAs production, including mango seed fat, bambangan kernel fat, shea butter, kokum butter, sunflower stearin and palm oil fractions such as palm oil mid fraction and palm stearin are highlighted. The potential application of the blended fat as CBAs and the changes in their physicochemical, thermal and morphological behaviour are discussed. Key findings and conclusions The blended fats and oils produced from different sources greatly resemble the characteristics of commercial CB with improved thermal and bloom properties. Thus, the blending processes facilitated the application of various vegetable fats and oils as CBAs to improve the physical quality of the final product in the manufacture of chocolates and confectioneries.

Most human influenza vaccine antigens are produced in fertilized chicken eggs. Recent H3N2 egg-based vaccine antigens have limited effectiveness, partially due to egg-adaptive substitutions that alter the antigenicity of the hemagglutinin (HA) protein. The nucleoside-modified messenger RNA encapsulated in lipid nanoparticle (mRNA-LNP) vaccine platform is a promising alternative for egg-based influenza vaccines because mRNA-LNP-derived antigens are not subject to adaptive pressures that arise during the production of antigens in chicken eggs. Here, we compared H3N2-specific antibody responses in mice vaccinated with either 3c.2A H3-encoded mRNA-LNP or a conventional egg-based Fluzone vaccine (which included an egg-adapted 3c.2A antigen) supplemented with an MF59-like adjuvant. We tested mRNA-LNP encoding wild-type and egg-adapted 3c.2A H3 antigens. We found that mRNA-LNP encoding wild-type 3c.2A H3 elicited antibodies that neutralized the wild-type 3c.2A H3N2 virus more effectively relative to antibodies elicited by mRNA-LNP encoding egg-adapted 3c2.A H3 or the egg-based Fluzone vaccine. mRNA-LNP expressing either wild-type or egg-adapted 3c2.A H3 protected mice against infection with the wild-type 3c2.A H3N2, whereas the egg-based Fluzone vaccine did not. We found that both mRNA-LNP vaccines elicited high levels of group 2 HA stalk-reactive antibodies that likely contributed to protection in vivo. Our studies indicate that nucleoside-modified mRNA-LNP-based vaccines can circumvent problems associated with egg-adaptations with recent 3c2.A H3N2 viruses.SummaryThis study shows that the nucleoside-modified messenger RNA encapsulated in lipid nanoparticle (mRNA-LNP) vaccine platform is a promising alternative for egg-based influenza vaccines. We show that mRNA-LNP expressing H3 antigens elicit high levels of antibodies in mice and protect against H3N2 influenza virus infection.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare disease caused by recessive mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase (TP). In this study,...

Background: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare and progressive disease caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase (TP). This results in a systemic accumulation of nucleosides and mitochondrial toxicity. AAV-based liver-directed gene therapy has shown efficacy in preclinical studies, but it has limitations such as a decline of transgene expression long-term. We propose that gene editing can circumvent some of these problems. Methods: We performed a preclinical study in the murine model of MNGIE to assess that the coordinated delivery of CRISPR/Cas9 and a TYMP cDNA caused the efficient integration of a TYMP transgene into introns of the Tymp and Alb loci in hepatocytes. CRISPR/Cas9 was delivered either as mRNA using nanoparticles or in AAV2/8 viral vectors; the latter were also used to package the TYMP cDNA. We assessed the efficient integration of the templates into the liver cells, and monitored the nucleoside levels in plasma to detect the biochemical correction. Findings: The best results were obtained using lipid nanoparticles. The consistent and stable nucleoside reduction observed correlated with the presence of TYMP mRNA and functional enzyme in the liver cells. In mice with an edited Alb locus, the transgene produced a hybrid Alb-hTP protein that was secreted, with high levels of TP activity in plasma. Interpretation: Liver-directed gene editing is a feasible approach to achieve the long-term biochemical correction of the disease, with several advantages over previous methods. Funding Information: This project was made possible with financial support from the Instituto de Salud Carlos III/FEDER (grant PI15/00172) and from MINECO/FEDER (grant RTI2018-094734-B-C22). The support of the Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR) of the Generalitat de Catalunya, through SGR 2017 1559 grant, is also acknowledged. Declaration of Interests: S.H.Y.F. and Y.K.T. are employees of Acuitas Therapeutics, a company focused on the development of lipid nanoparticle delivery systems for nucleic-acid-based drugs. RM was the recipient of personal fees associated with advisory tasks and of financial support from Modis Therapeutics for research outside the submitted work. RM also holds a patent “Deoxynucleoside therapy for diseases caused by unbalanced nucleotide pools including mitochondrial DNA depletion syndromes” (PCT/US16/038110), with royalties paid to Modis Therapeutics. INCOMPLETE Ethics Approval Statement: All animal procedures were performed in accordance with European recommendations and were approved by our institutional ethics committee (Comite Etic d’Experimentacio Animal).

The deployment of effective vaccines against SARS-CoV-2 is critical to eradicate the COVID-19 pandemic. Many licensed vaccines confer protection by inducing long-lived plasma cells (LLPC) and memory B cells (MBC), cell types canonically generated during germinal center (GC) reactions. Here, we directly compared two vaccine platforms −mRNA vaccines and a recombinant protein formulated with an MF59-like adjuvant− for their ability to quantitatively and qualitatively shape SARS-CoV-2-specific primary GC responses over time. We demonstrated that a single immunization with SARS-CoV-2 mRNA, but not with the recombinant protein vaccine, elicited potent SARS-CoV-2-specific GC B and T follicular helper (Tfh) cell responses as well as LLPC and MCB. Importantly, GC responses strongly correlated with neutralizing antibody production. mRNA vaccines more efficiently induced key regulators of the Tfh cell program and influenced the functional properties of Tfh cells. Overall, this study identifies SARS-CoV-2 mRNA vaccines as strong candidates for promoting robust GC-derived immune responses., Graphical Abstract, Highlights • SARS-CoV-2 mRNA vaccines elicit potent germinal center (GC) B cell responses • GC responses are associated with a robust development of neutralizing antibodies • SARS-CoV-2 mRNA vaccines promote antigen-specific T follicular helper (Tfh) cells • Key elements of the Tfh cell program are modulated by SARS-CoV-2 mRNA vaccines, Herein, Lederer et al. show a nucleic acid-based vaccine platform for SARS-CoV-2 that potently induces germinal center (GC) responses. GC are microanatomical sites harboring the formation of high-quality, protective antibody responses. Such vaccine platforms can be promising candidates to mitigate the COVID-19 pandemic.

Molecular dynamics simulations of nanoindentation using a spherical indenter were adopted to quantitatively probe the local mechanical heterogeneity (MH) in Zr-Cu and Zr-Cu-Al metallic glasses. Distinct MH at the nanometer scale has been revealed by statistically analyzing the first pop-in stress of different regions in the metallic glasses with an indenter of 4 nm in diameter. More interestingly, it is found that the degree of MH has a close relation to glass-forming ability of alloys, i.e., the smaller MH, the better glass-forming ability. Our findings not only shed light on the intrinsic feature of atomic structures, but also have important implications in understanding the structure-property relationship of MGs.

We introduce new representations to formulate quantum mechanics on noncommutative coordinate space, which explicitly display entanglement properties between degrees of freedom of different coordinate components and hence could be called entangled state representations. Furthermore, we derive unitary transformations between the new representations and the ordinary one used in noncommutative quantum mechanics (NCQM) and obtain eigenfunctions of some basic operators in these representations. To show the potential applications of the entangled state representations, a two-dimensional harmonic oscillator on the noncommutative plane with both coordinate-coordinate and momentum-momentum couplings is exactly solved.

Synopsis The dependence of carrier lifetime on temperature has been investigated for n-type and p-type germanium. It is found that with decreasing temperature the lifetime decreases, but much faster in n-type than in p-type. The results are discussed in terms of recombination through trapping states. At sufficiently low temperatures photoconductivity and carrier injection experiments show signs of minority carrier trapping in n-type samples and occasionally in p-type samples. The phenomena observed are discussed and the properties of the trapping states are deduced. These particular trapping states are shown to be not the major cause of recombination. Doping with copper or thermally quenching n-type samples gives rise to trapping as well as enhances recombination. In comparison, thermal quenching can produce more effect on the lifetime with less effect on the sample resistivity.

Oscillation of the intrinsic photoconductivity with wavelength was observed in n-type InSb. Interpretation is given taking into account carrier trapping. Additional hot carrier effects were found in the dependence of photoconductivity on the applied electric field.

Publisher Summary Germanium and silicon crystals are the semiconductors that have been studied most intensively in the past decade. The importance of their practical applications—that began with the development of microwave rectifiers and expanded greatly with the discovery of transistor action—helped to stimulate the intensive research. As a result, rapid progress has been made in the knowledge of the elements and the general understanding of semiconductors. This chapter discusses what has been learned about the properties of these crystals t o the beginning of 1955. Many interesting properties are associated with nonuniform regions in the crystals, p-n junctions, and with the surfaces of the crystals. Such properties are important for practical applications of the semiconductors and a large amount of work has been devoted to their investigation. This chapter discusses bulk properties of uniform crystals. A brief summary of the theory of semiconductors is given in this chapter. It discusses various properties of the crystals that do not involve transport or nonequilibrium distribution of electrons. Conduction phenomena are discussed and problems connected with nonequilibrium electron distribution—that is, hole-electron recombination and carrier trapping, are also discussed in this chapter.

Publisher Summary This chapter discusses the effects of free carriers on the optical properties. In semiconductors, the effect of free carriers on the optical properties becomes important at wavelengths longer than the intrinsic absorption edge. Free carriers produce absorption and affect the dispersion at sufficiently long wavelengths. In a radiation field, the current of the carriers has a component in phase and a component out of phase with the electric field. The in-phase current contributes to the conductivity and the out-of-phase component contributes to the susceptibility. In terms of the electronic energy bands of the crystal, the effects of the carriers may be intraband or interband in nature. The intraband effects involve only the energy band that contains the carriers, and will be simply referred to as free-carrier effects. The interband effects involve another energy band.

The effects of phonon assisted transitions and longitudinal optical phonon emission by excited carriers are observed in the impurity photoconductivity of ZnTe at low temperatures.

Some recent investigations of infrared absorption associated with lattice imperfections in germanium and silicon are reported. The ionization and excitation bands of group III and group V impurities in germanium were observed at liquid helium temperature and long wavelengths, up to 300 microns. Ionization energies are deduced which are close to the values given by electrical measurements. A number of excitation bands were observed in each case. The spectra of the impurities are compared with each other and with the theoretical calculations of kohn. The experimental results can be interpreted on the basis of the theory to a certain extent but give extra excitation bands which cannot be explained by the theoretical calculation. The effects of different factors, such as the concentration of impurities, have been studied. Irradiation by high energy neutrons and electrons produces in silicon infrared absorption bands associated with the introduced lattice defects. Several bands have been observed. The possibility of observing a particular absorption band depends on the Fermi level in the irradiated sample which determines the state of ionization of the defects. The absorption was studied after annealing the sample at different temperatures. It was found that the various absorption bands are associated with different types of defect centers. One of the bands, at 20.5 microns, increased or decreased with temperature annealing, depending on the Fermi level. The observation is understandable on the assumption that the anneal of the type of absorption center depends upon the state of ionization of the defects.