Discovery of a novel highly specific, fully human PSCA antibody and its application as an antibody-drug conjugate in prostate cancer.

Prostate stem cell antigen (PSCA) is expressed in all stages of prostate cancer, including in advanced androgen-independent tumors and bone metastasis. PSCA may associate with prostate carcinogenesis and lineage plasticity in prostate cancer. PSCA is also a promising theranostic marker for a variety of other solid tumors, including pancreatic adenocarcinoma and renal cell carcinoma. Here, we identified a novel fully human PSCA antibody using phage display methodology. The structure-based affinity maturation yielded a high-affinity binder, F12, which is highly specific and does not bind to 6,000 human membrane proteins based on a membrane proteome array assay. F12 targets PSCA amino acids 63-69 as tested by the peptide scanning microarray, and it cross-reacts with the murine PSCA. IgG1 F12 efficiently internalizes into PSCA-expressing tumor cells. The antimitotic reagent monomethyl auristatin E (MMAE)-conjugated IgG1 F12 (ADC, F12-MMAE) exhibits dose-dependent efficacy and specificity in a human prostate cancer PC-3-PSCA xenograft NSG mouse model. This is a first reported ADC based on a fully human PSCA antibody and MMAE that is characterized in a xenograft murine model, which warrants further optimizations and investigations in additional preclinical tumor models, including prostate and other solid tumors.

Efficient solar-driven CO2-to-fuel conversion via Ni/MgAlO x @SiO2 nanocomposites at low temperature.

Solar-driven CO2-to-fuel conversion assisted by another major greenhouse gas CH4 is promising to concurrently tackle energy shortage and global warming problems. However, current techniques still suffer from drawbacks of low efficiency, poor stability, and low selectivity. Here, a novel nanocomposite composed of interconnected Ni/MgAlO x nanoflakes grown on SiO2 particles with excellent spatial confinement of active sites is proposed for direct solar-driven CO2-to-fuel conversion. An ultrahigh light-to-fuel efficiency up to 35.7%, high production rates of H2 (136.6 mmol min-1g- 1) and CO (148.2 mmol min-1g-1), excellent selectivity (H2/CO ratio of 0.92), and good stability are reported simultaneously. These outstanding performances are attributed to strong metal-support interactions, improved CO2 absorption and activation, and decreased apparent activation energy under direct light illumination. MgAlO x @SiO2 support helps to lower the activation energy of CH* oxidation to CHO* and improve the dissociation of CH4 to CH3* as confirmed by DFT calculations. Moreover, the lattice oxygen of MgAlO x participates in the reaction and contributes to the removal of carbon deposition. This work provides promising routes for the conversion of greenhouse gasses into industrially valuable syngas with high efficiency, high selectivity, and benign sustainability.

Ultrastable halide perovskite CsPbBr3 photoanodes achieved with electrocatalytic glassy-carbon and boron-doped diamond sheets.

Halide perovskites exhibit exceptional optoelectronic properties for photoelectrochemical production of solar fuels and chemicals but their instability in aqueous electrolytes hampers their application. Here we present ultrastable perovskite CsPbBr3-based photoanodes achieved with both multifunctional glassy carbon and boron-doped diamond sheets coated with Ni nanopyramids and NiFeOOH. These perovskite photoanodes achieve record operational stability in aqueous electrolytes, preserving 95% of their initial photocurrent density for 168 h of continuous operation with the glassy carbon sheets and 97% for 210 h with the boron-doped diamond sheets, due to the excellent mechanical and chemical stability of glassy carbon, boron-doped diamond, and nickel metal. Moreover, these photoanodes reach a low water-oxidation onset potential close to +0.4 VRHE and photocurrent densities close to 8 mA cm-2 at 1.23 VRHE, owing to the high conductivity of glassy carbon and boron-doped diamond and the catalytic activity of NiFeOOH. The applied catalytic, protective sheets employ only earth-abundant elements and straightforward fabrication methods, engineering a solution for the success of halide perovskites in stable photoelectrochemical cells.

Swept coded aperture real-time femtophotography.

Single-shot real-time femtophotography is indispensable for imaging ultrafast dynamics during their times of occurrence. Despite their advantages over conventional multi-shot approaches, existing techniques confront restricted imaging speed or degraded data quality by the deployed optoelectronic devices and face challenges in the application scope and acquisition accuracy. They are also hindered by the limitations in the acquirable information imposed by the sensing models. Here, we overcome these challenges by developing swept coded aperture real-time femtophotography (SCARF). This computational imaging modality enables all-optical ultrafast sweeping of a static coded aperture during the recording of an ultrafast event, bringing full-sequence encoding of up to 156.3 THz to every pixel on a CCD camera. We demonstrate SCARF's single-shot ultrafast imaging ability at tunable frame rates and spatial scales in both reflection and transmission modes. Using SCARF, we image ultrafast absorption in a semiconductor and ultrafast demagnetization of a metal alloy.

Coseismic Deformation Field and Fault Slip Distribution Inversion of the 2020 Jiashi Ms 6.4 Earthquake: Considering the Atmospheric Effect with Sentinel-1 Data Interferometry.

Due to some limitations associated with the atmospheric residual phase in Sentinel-1 data interferometry during the Jiashi earthquake, the detailed spatial distribution of the line-of-sight (LOS) surface deformation field is still not fully understood. This study, therefore, proposes an inversion method of coseismic deformation field and fault slip distribution, taking atmospheric effect into account to address this issue. First, an improved inverse distance weighted (IDW) interpolation tropospheric decomposition model is utilised to accurately estimate the turbulence component in tropospheric delay. Using the joint constraints of the corrected deformation fields, the geometric parameters of the seismogenic fault and the distribution of coseismic slip are then inverted. The findings show that the coseismic deformation field (long axis strike was nearly east-west) was distributed along the Kalpingtag fault and the Ozgertaou fault, and the earthquake was found to occur in the low dip thrust nappe structural belt at the subduction interface of the block. Correspondingly, the slip model further revealed that the slips were concentrated at depths between 10 and 20 km, with a maximum slip of 0.34 m. Accordingly, the seismic magnitude of the earthquake was estimated to be Ms 6.06. Considering the geological structure in the earthquake region and the fault source parameters, we infer that the Kepingtag reverse fault is responsible for the earthquake, and the improved IDW interpolation tropospheric decomposition model can perform atmospheric correction more effectively, which is also beneficial for the source parameter inversion of the Jiashi earthquake.

Revealing the stochastic kinetics evolution of photocatalytic CO2 reduction.

Investigating kinetic mechanisms to design efficient photocatalysts is critical for improving photocatalytic CO2 reduction, but the stochastic photo-physical/chemical properties of kinetics remain unclear. Herein, we propose a statistical study to discuss the stochastic feature evolution of photocatalytic systems. The uncertainties of light absorption, charge carrier migration, and surface reaction are described by nonparametric estimation methods in the proposed model, which includes the effect of operational and material parameters. The density distribution of surface electrons shifts from a skewed distribution to an approximate uniform distribution as incident photon density increases. The system temperature rising induces the rate-determining step of surface reactions to change from charge carrier kinetics to reactant activation processes. Benefiting from the synergistic optimization between the operational parameter and active site density, the electron-capturing probability of active sites is boosted from 0.06 to 0.17. The modified reaction kinetic equation is constructed based on the distribution function of charge carrier kinetics. Furthermore, the experimental photoactivity results are consistent with the statistical analysis, which proves the feasibility of the established model. The characterization tests show that the gap between testing activities and theoretical efficiency is caused by a mismatch between charge carrier supply and mass transfer. Our work unveils the stochastic features in photocatalytic CO2 reduction, offering a comprehensive analytical framework for photocatalytic system optimization.

Single-shot compressed optical field topography.

Femtosecond lasers are powerful in studying matter's ultrafast dynamics within femtosecond to attosecond time scales. Drawing a three-dimensional (3D) topological map of the optical field of a femtosecond laser pulse including its spatiotemporal amplitude and phase distributions, allows one to predict and understand the underlying physics of light interaction with matter, whose spatially resolved transient dielectric function experiences ultrafast evolution. However, such a task is technically challenging for two reasons: first, one has to capture in single-shot and squeeze the 3D information of an optical field profile into a two-dimensional (2D) detector; second, typical detectors are only sensitive to intensity or amplitude information rather than phase. Here we have demonstrated compressed optical field topography (COFT) drawing a 3D map for an ultrafast optical field in single-shot, by combining the coded aperture snapshot spectral imaging (CASSI) technique with a global 3D phase retrieval procedure. COFT can, in single-shot, fully characterize the spatiotemporal coupling of a femtosecond laser pulse, and live stream the light-speed propagation of an air plasma ionization front, unveiling its potential applications in ultrafast sciences.

Synergistic surface oxygen defect and bulk Ti3+ defect engineering on SrTiO3 for enhancing photocatalytic overall water splitting.

SrTiO3 as a photocatalytic overall water splitting material has received extensive attention in recent years, while effectively suppressing Ti3+ is the key to enhancing the photocatalytic performance. Herein, a polymerizable complexation method is employed to enable Al3+ uniformly enter into SrTiO3 lattice for reducing Ti3+, and substituting Ti4+ with the formation of oxygen vacancy. Thus, the photogenerated carrier transport is promoted, and the resulting appropriate surface oxygen vacancy is also conducive to the adsorption of water molecules and OH*. The optimized 2% Al3+-doped SrTiO3 possesses a lower Ti3+ concentration, compared with the same sample prepared by the solid-phase griding method. Consequently, 2% Al-STO sample deposited co-catalysts achieves the highest activity and durability with the H2 and O2 evolution rates of 1.256 mmol·h-1 and 0.692 mmol·h-1 (0.04 g catalyst), respectively, corresponding to the AQE value of 55.46% at 365 nm. The characterizations and DFT calculation results reveal that the uniform Al3+ doping promotes the increase in the surface oxygen vacancy, which is beneficial for accelerating the reduction reaction and facilitating carrier separation and migration, therefore enhancing the overall water splitting reaction.

Potent and broad neutralization of SARS-CoV-2 variants of concern (VOCs) including omicron sub-lineages BA.1 and BA.2 by biparatopic human VH domains.

The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics with high neutralization breadth. Here, we characterized a human VH domain, F6, which we generated by sequentially panning large phage-displayed VH libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized VH domain, resulted in a construct (F6-ab8-Fc) that broadly and potently neutralized VOCs including Omicron. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 variants including Omicron and highlight a vulnerable epitope within the spike that may be exploited to achieve broad protection against circulating variants.

What Role Does the Incident Light Intensity Play in Photocatalytic Conversion of CO2 : Attenuation or Intensification?

Artificial photoreduction of CO2 is vital for the sustainable development of human beings via solar energy storage in stable chemicals. This process involves intricate light-matter interactions, but the role of incident light intensity in photocatalysis remains obscure. Herein, the influence of excitation intensity on charge kinetics and photocatalytic activity is investigated. Model photocatalysts include the pure graphitic carbon nitride (g-C3 N4 ) and g-C3 N4 loaded with noble/non-noble-metal cocatalysts (Ag, TiN, and CuO). It is found that the increase of light intensity does not always improve the electron utilization. Overly high excitation intensities cause charge carrier congestion and changes the recombination mechanism, which is called the light congestion effect. The electron transport channels can be established to mitigate the light-induced effect via the addition of cocatalyst, leading to a nonlinear growth in the reaction rate with increasing light intensity. From experiments and simulations, it is found that the light intensity and active site density should be collectively optimized for increasing the energy conversion efficiency. This work elucidates the effect of light intensity on photocatalytic CO2 reduction and emphasizes the synergistic relationship of matching the light intensity and the photocatalyst category. The study provides guidance for the design of efficient photocatalysts and the operation of photocatalytic systems.

Potent Neutralization of Omicron and other SARS-CoV-2 Variants of Concern by Biparatopic Human VH Domains.

The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics that are effective against a variety of strains of the virus. Herein, we characterize a human V H domain, F6, which we generated by sequentially panning large phage displayed V H libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized V H domain, resulted in a construct (F6-ab8-Fc) that neutralized Omicron pseudoviruses with a half-maximal neutralizing concentration (IC 50 ) of 4.8 nM in vitro . Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 VOCs - including the recently emerged Omicron variant - and highlight a vulnerable epitope within the spike protein RBD that may be exploited to achieve broad protection against circulating variants.

Fast wide-field upconversion luminescence lifetime thermometry enabled by single-shot compressed ultrahigh-speed imaging.

Photoluminescence lifetime imaging of upconverting nanoparticles is increasingly featured in recent progress in optical thermometry. Despite remarkable advances in photoluminescent temperature indicators, existing optical instruments lack the ability of wide-field photoluminescence lifetime imaging in real time, thus falling short in dynamic temperature mapping. Here, we report video-rate upconversion temperature sensing in wide field using single-shot photoluminescence lifetime imaging thermometry (SPLIT). Developed from a compressed-sensing ultrahigh-speed imaging paradigm, SPLIT first records wide-field luminescence intensity decay compressively in two views in a single exposure. Then, an algorithm, built upon the plug-and-play alternating direction method of multipliers, is used to reconstruct the video, from which the extracted lifetime distribution is converted to a temperature map. Using the core/shell NaGdF4:Er3+,Yb3+/NaGdF4 upconverting nanoparticles as the lifetime-based temperature indicators, we apply SPLIT in longitudinal wide-field temperature monitoring beneath a thin scattering medium. SPLIT also enables video-rate temperature mapping of a moving biological sample at single-cell resolution.

Effective killing of cells expressing CD276 (B7-H3) by a bispecific T cell engager based on a new fully human antibody.

The pancaner molecule CD276 (B7-H3) is an attractive target for antibody based therapy. We identified from a large (1011) phage-displayed single-chain variable fragment (scFv) library, a fully human antibody, B11, which bound with high avidity (KD=0.4 nM) to CD276. B11 specifically bound to the V1/V2 domain of CD276 and competed with the antibody 8H9 (Omburtamab). It was used to design an IgG-format bispecific T cell engager B11-BiTE, which was more effective than 8H9-BiTE in 14 different cancer cell lines. B11-BiTE also exhibited strong ADCC/ADCP. Therefore, the fully human B11-BiTE is a promising candidate for treatment of tumors expressing CD276.

Structural details of monoclonal antibody m971 recognition of the membrane-proximal domain of CD22.

Cluster of differentiation-22 (CD22) belongs to the sialic acid-binding immunoglobulin (Ig)-like lectin family of receptors that is expressed on the surface of B cells. It has been classified as an inhibitory coreceptor for the B-cell receptor because of its function in establishing a baseline level of B-cell inhibition. The restricted expression of CD22 on B cells and its inhibitory function make it an attractive target for B-cell depletion in cases of B-cell malignancies. Genetically modified T cells with chimeric antigen receptors (CARs) derived from the m971 antibody have shown promise when used as an immunotherapeutic agent against B-cell acute lymphoblastic leukemia. A key aspect of the efficacy of this CAR-T was its ability to target a membrane-proximal epitope on the CD22 extracellular domain; however, the molecular details of m971 recognition of CD22 have thus far remained elusive. Here, we report the crystal structure of the m971 fragment antigen-binding in complex with the two most membrane-proximal Ig-like domains of CD22 (CD22d6-d7). The m971 epitope on CD22 resides at the most proximal Ig domain (d7) to the membrane, and the antibody paratope contains electrostatic surfaces compatible with interactions with phospholipid head groups. Together, our data identify molecular details underlying the successful transformation of an antibody epitope on CD22 into an effective CAR immunotherapeutic target.

Protocol for constructing large size human antibody heavy chain variable domain (VH) library and selection of SARS-CoV-2 neutralizing antibody domains.

This protocol is a comprehensive guide to phage display-based selection of virus neutralizing VH antibody domains. It details three optimized parts including (1) construction of a large-sized (theoretically > 1011) naïve human antibody heavy chain domain library, (2) SARS-CoV-2 antigen expression and stable cell line construction, and (3) library panning for selection of SARS-CoV-2-specific antibody domains. Using this protocol, we identified a high-affinity neutralizing human VH antibody domain, VH ab8, which exhibits high prophylactic and therapeutic efficacy. For complete details on the use and execution of this protocol, please refer to Li et al. (2020).

The reduced form of the antibody CH2 domain.

Among the immunoglobulin domains, the CH2 domain has the lowest thermal stability, which also depends on amino acid sequence and buffer conditions. To further identify factors that influence CH2 folding and stability, we characterized the domain in the reduced form using differential scanning fluorimetry and nuclear magnetic resonance. We show that the CH2 domain can fold, similarly to the disulfide-bridged form, without forming a disulfide-bridge, even though the protein contains two Cys residues. Although the reduced form exhibits thermal stability more than 15°C lower than the disulfide-bridged form, it does not undergo immediate full oxidization. To explain this phenomenon, we compared CH2 oxidization at different conditions and demonstrate a need for significant fluctuation of the folded conformation to enhance CH2 disulfide-bridge formation. We conclude that, since CH2 can be purified as a folded, semi-stable, reduced protein that can coexist with the oxidized form, verification of the level of oxidization at each step is critical in CH2 engineering studies.

Highly Selective Production of Ethanol Over Hierarchical Bi@Bi2 MoO6 Composite via Bicarbonate-Assisted Photocatalytic CO2 Reduction.

Photocatalytic CO2 reduction is a sustainable and inexpensive method to solve the energy crisis and the greenhouse effect. However, the major stumbling blocks such as poor product selectivity, low yield of the multi-carbon products, and serious recombination of electron-hole pairs hinder practical application of photocatalysts. Herein, a high-performance Bi@Bi2 MoO6 photocatalyst, Bi nanoparticles grown on the surface of Bi2 MoO6 nanosheets with oxygen vacancies, was fabricated via a simple solvothermal approach. Benefiting from the abundant active sites and effective separation of photogenerated carriers of Bi2 MoO6 nanosheets, and the localized surface plasmon resonance effect of Bi nanoparticles, the Bi@Bi2 MoO6 sample exhibited great photocatalytic CO2 reduction activity. Furthermore, adding NaHCO3 into the system not only significantly increased the C2 H5 OH generation rate but also enhanced the product selectivity. In the photocatalytic measurement (0.17 mol L-1 CO2 -saturated NaHCO3 solution), the highest formation rates of CO, CH3 OH, and C2 H5 OH were reached at 0.85, 0.59, and 17.93 µmol g-1 h-1 (≈92 % selectivity), respectively.

Compressed ultrafast tomographic imaging by passive spatiotemporal projections.

Existing streak-camera-based two-dimensional (2D) ultrafast imaging techniques are limited by long acquisition time, the trade-off between spatial and temporal resolutions, and a reduced field of view. They also require additional components, customization, or active illumination. Here we develop compressed ultrafast tomographic imaging (CUTI), which passively records 2D transient events with a standard streak camera. By grafting the concept of computed tomography to the spatiotemporal domain, the operations of temporal shearing and spatiotemporal integration in a streak camera's data acquisition can be equivalently expressed as the spatiotemporal projection of an (x,y,t) datacube from a certain angle. Aided by a new, to the best of our knowledge, compressed-sensing reconstruction algorithm, the 2D transient event can be accurately recovered in a few measurements. CUTI is exhibited as a new imaging mode universally adaptable to most streak cameras. Implemented in an image-converter streak camera, CUTI captures the sequential arrival of two spatially modulated ultrashort ultraviolet laser pulses at 0.5 trillion frames per second. Applied to a rotating-mirror streak camera, CUTI records an amination of fast-bouncing balls at 5,000 frames per second.

Extraction of a Weak Flow Field for a Multi-Rotor Unmanned Aerial Vehicle (UAV) Using High-Speed Background-Oriented Schlieren (BOS) Technology.

To optically capture and analyze the structure and changes of the flow field of a weak airflow object with high accuracy, this study proposes novel weak flow field extraction methods based on background-oriented schlieren. First, a fine background pattern texture and a sensor network layout were designed to satisfy the requirement of weak flow field extraction. Second, the image displacement was extracted by calculating the correlation matrix in the frequency domain for a particle image velocimetry algorithm, and further calculations were performed for the density field using Poisson's equation. Finally, the time series baseline stacking method was proposed to obtain the flow field changes of weak airflow structures. A combustion experiment was conducted to validate the feasibility and accuracy of the proposed method. The results of a quad-rotor unmanned aerial vehicle experiment showed that the clear, uneven, and continuous quantitative laminar flow field could be obtained directly, which overcame the interference of the weak airflow, large field of view, and asymmetrical steady flow.

Developability Assessment of an Isolated CH2 Immunoglobulin Domain.

The IgG CH2 domain continues to hold promise for the development of new therapeutic entities because of its bifunctional role as a biomarker and effector protein. The need for further understanding of molecular stability and aggregation in therapeutic proteins has led to the development of a breakthrough quantum cascade laser microscope to allow for real-time comparability assessment of an array of related proteins in solution upon thermal perturbation. Our objective was to perform a comprehensive developability assessment of three similar monoclonal antibody (mAb) fragments: CH2, CH2s, and m01s. The CH2 construct consists of residues Pro238 to Lys340 of the IgG1 heavy chain sequence. CH2s has a 7-residue deletion at the N-terminus and a 16-residue C-terminal extension containing a histidine tag. The m01s construct is identical to CH2s, except for two cysteines introduced at positions 242 and 334. A series of hyperspectral images was acquired during thermal perturbation from 28 to 60 °C for all three proteins in an array. Co-distribution and two-dimensional infrared correlation spectroscopies yielded the mechanism of aggregation and stability for these three proteins. The level of detail is unprecedented, identifying the regions within CH2 and CH2s that are prone to self-association and establishing the differences in stability. Furthermore, CH2 helical segments, ß-sheets, ß-turns, and random coil regions were less stable than in CH2s and m01s because of the presence of the N-terminal 310-helix and ß-turn type III. The engineered disulfide bridge in m01s eliminated the self-association process and rendered this mAb fragment the most stable.