Attenuation of Heparan Sulfate Proteoglycan Binding Enhances In Vivo Transduction of Human Primary Hepatocytes with AAV2

Use of the prototypical adeno-associated virus type 2 (AAV2) capsid delivered unexpectedly modest efficacy in an early liver-targeted gene therapy trial for hemophilia B. This result is consistent with subsequent data generated in chimeric mouse-human livers showing that the AAV2 capsid transduces primary human hepatocytes in vivo with low efficiency. In contrast, novel variants generated by directed evolution in the same model, such as AAV-NP59, transduce primary human hepatocytes with high efficiency. While these empirical data have immense translational implications, the mechanisms underpinning this enhanced AAV capsid transduction performance in primary human hepatocytes are yet to be fully elucidated. Remarkably, AAV-NP59 differs from the prototypical AAV2 capsid by only 11 aa and can serve as a tool to study the correlation between capsid sequence/structure and vector function. Using two orthogonal vectorological approaches, we have determined that just 2 of the 11 changes present in AAV-NP59 (T503A and N596D) account for the enhanced transduction performance of this capsid variant in primary human hepatocytes in vivo, an effect that we have associated with attenuation of heparan sulfate proteoglycan (HSPG) binding affinity. In support of this hypothesis, we have identified, using directed evolution, two additional single amino acid substitution AAV2 variants, N496D and N582S, which are highly functional in vivo. Both substitution mutations reduce AAV2's affinity for HSPG. Finally, we have modulated the ability of AAV8, a highly murine-hepatotropic serotype, to interact with HSPG. The results support our hypothesis that enhanced HSPG binding can negatively affect the in vivo function of otherwise strongly hepatotropic variants and that modulation of the interaction with HSPG is critical to ensure maximum efficiency in vivo. The insights gained through this study can have powerful implications for studies into AAV biology and capsid development for preclinical and clinical applications targeting liver and other organs

Echo Extraction from an Ultrasonic Signal Using Continuous Wavelet Transform

Wavelet transform has already been shown as a useful tool for the interpretation and the enhancement of ultrasonic data in the context of nondestructive evaluation [1–3]. Main applications of the wavelet transform are signal analysis in the time-frequency domain, data compression and now signal processing. Comparisons with other time-frequency representations like short time Fourier transform [1] and Wigner-ville transform [2] have shown the usefulness of the continuous wavelet transform for signal analysis: this method is well adapted to localize in time both high and low frequencies and does not introduce interference terms. Another important property is that signal reconstruction can be achieved from wavelet decomposition. This ability allows one to do signal processing in the time-frequency plane. Earlier work has shown the possibilities to use the wavelet transform as a filter for signal-to-noise ratio enhancement [2] by reconstructing the signal after applying energy thresholding in the time-frequency domain. This reconstruction does not involve global averaging in time or frequency domain because of the good localization of the wavelet coefficients in both domains.</p

Ligand influence in Li-ion battery hybrid active materials: Ni methylenediphosphonate vs. Ni dimethylamino methylenediphosphonate

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Photocatalytic performance of mesoporous TiO2 films doped with gold clusters

We report on the single-pot fabrication of ordered mesoporous crystallized titania films doped with gold. Au is incorporated in TiO2 films by adding to the coating solution precursors such as AuCl3 or monodisperse Au113+ nanoclusters, and Au nanoparticles are formed by calcination. A systematic study is performed to correlate structure, Au doping and photocatalytic activity of such films. Two-dimensional small angle X-ray scattering (2D-SAXS), transmission electronic microscopy (TEM), scanning electronic microscopy (SEM) and porosimetry\u2013ellipsometry show that the films retain their mesoporous order even for doping levels as high as 1% Au\u2006:\u2006Ti atomic ratio. Wide angle X-ray scattering (WAXS), and cyclovoltammetry (CV) show that Au113+ nanoclusters promote the formation of the TiO2 (B) phase in competition with the anatase phase. AuCl3 stabilizes instead only the anatase phase. The highest photocatalytic activity is exhibited by films where Au113+ is employed as a precursor, which we attribute to the combination of the mixed anatase/TiO2 (B) phase, of Au nanoparticle doping and of a well-ordered mesoporous TiO2 matrix

DBD plasma‐assisted coating of metal alkoxides on sulfur powder for Li–S batteries

Abstract Sulfur particles coated by activation of metal alkoxide precursors, aluminum–sulfur (Alu–S) and vanadium–sulfur (Van–S), were produced by dielectric barrier discharge (DBD) plasma technology under low temperature and ambient pressure conditions. We report a safe, solvent‐free, low‐cost, and low‐energy consumption coating process that is compatible for sustainable technology up‐scaling. NMR, XPS, SEM, and XRD characterization methods were used to determine the chemical characteristics and the superior behavior of Li–S cells using metal oxide‐based coated sulfur materials. The chemical composition of the coatings is a mixture of the different elements present in the metal alkoxide precursor. The presence of alumina Al2O3 within the coating was confirmed. Multi‐C rate and long‐term galvanostatic cycling at rate C/10 showed that the rate capability losses and capacity fade could be highly mitigated for the Li–S cells containing the coated sulfur materials in comparison to the references uncoated (raw) sulfur. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) confirm the lower charge‐transfer resistance and potential hysteresis in the electrodes containing the coated sulfur particles. Our results show that the electrochemical performance of the Li–S cells based on the different coating materials can be ranked as Alu‐S > Van‐S > Raw sulfur