Structure–Activity Relationships of JMV4463, a Vectorized Cathepsin D Inhibitor with Antiproliferative Properties: The Unique Role of the AMPA‐Based Vector

Cathepsin D (CathD) is overexpressed and secreted by several solid tumors and stimulates their growth, the mechanism of which is still not understood. In this context, the pepstatin bioconjugate JMV4463 [Ac‐arg‐O₂Oc‐(Val)₃‐Sta‐Ala‐Sta‐(AMPA)₄‐NH₂; O₂Oc=8‐amino‐3,6‐dioxaoctanoyl, Sta=statine, AMPA=ortho‐aminomethylphenylacetyl], containing a new kind of cell‐penetrating vector, was previously shown to exhibit potent antiproliferative effects in vitro and to delay the onset of tumors in vivo. In this study, we performed a structure–activity relationship analysis to evaluate the significance of the inhibitor and vector moieties of JMV4463. By modifying both statine residues of pepstatin we found that the antiproliferative activity is correlated with CathD inhibition, supporting a major role of the catalytic activity of intracellular CathD in cancer cell proliferation. Replacing the vector composed of four AMPA units with other vectors was found to abolish cytotoxicity, although all of the conjugates enabled pepstatin transport into cells. In addition, the AMPA₄ vector must be localized at the C terminus of the bioconjugate. The unexpected importance of the vector structure and position for cytotoxic action suggests that AMPA₄ enables pepstatin to inhibit the proteolysis of critical CathD substrates involved in cell proliferation via a unique mechanism of action.     

Separation of He/N2/CH4 ternary mixtures by a triple-reflux pressure swing adsorption process

Conventional pressure swing adsorption (PSA) processes can only produce one high purity product in a single stage, whereas the state-of-art dual-reflux PSA (DR-PSA) can produce two high purity products simultaneously. However, multicomponent gas separation is often required in the industry, targeting at recovering several valued products at the same time. In this study, we propose a novel adsorption process, namely triple-reflux PSA (TR-PSA), to separate three components simultaneously. A middle product outlet and a middle reflux stream were introduced to the adsorption columns of a conventional DR-PSA process to separate ternary mixtures of nitrogen, methane, and helium. Nonisothermal dynamic models were built to investigate the impacts of operating parameters particularly the location of the middle reflux/product stream and the middle reflux flow rates. Results showed that the TR-PSA process successfully separated ternary mixtures obtaining three enriched products simultaneously in a single stage, yielding a separation performance comparable to that of the double-stage DR-PSA with significantly lower capital and energy cost.     

Increased conversion efficiency in cadmium telluride photovoltaics by luminescent downshifting with quantum dot/poly(methyl methacrylate) films

Commercially available quantum dots have been encapsulated in a poly(methyl methacrylate) film and used as a luminescent downshifting layer on cadmium sulfide/cadmium telluride photovoltaic devices. Application of these films has resulted in a relative improvement to the short‐circuit current of over 4% by I–V measurement, with a significant increase in the contribution of short‐wavelength light resulting in 25% of the current available in this part of the spectrum being captured. The films have been shown to be highly scattering and the associated difficulties this provides to external quantum efficiency measurements have been discussed. A range of optical characterisation techniques, particularly laser beam induced current, have been used to probe the effect the films have on a cadmium sulfide/cadmium telluride device. An alternate methodology for performing external quantum efficiency measurements with the quantum dot films has been proposed. Copyright © 2013 John Wiley & Sons, Ltd.     

Mechanical Behavior of Nanostructured and Microstructured Explosives

Nanostructured hexolites (40/60), (60/40), (80/20) and microstructured hexolite (60/40) powders are pressed by uniaxial compression to obtain explosive charges. This kind of composition is often used for the synthesis of detonation nanodiamonds. The morphology, density and cohesion of the resulting pellets are analyzed in the light of the different used compression parameters. This study allows optimizing the compression parameters to obtain well suited explosive charges from nanostructured explosive components. A good cohesion of the nanostructured explosive pellets could be obtained with increasing the temperature used for the compression. Another very important point is that the nanostructuring of the composites is maintained for every compression.     

The impact of alkali elements on the degradation of CIGS solar cells

Unencapsulated CIGS solar cells with high and low contents of sodium (Na) and potassium (K) were simultaneously exposed to damp heat and illumination. The solar cells with a high alkali (Na, K) content exhibited higher initial conversion efficiencies, but degraded severely within 100 h, while the alkali poor samples kept relatively stable performance under damp heat and illumination. The degradation of the samples with a high alkali content resulted in the formation of sodium rich spots on the top ZnO:Al surface of the samples. This is likely caused by light‐induced Na⁺ migration via the grain boundaries in the absorber to the depletion region, where the Na⁺ accumulated. This allowed subsequent Na⁺ transport through the depletion region due to the lowering of the internal electric field caused both by the Na⁺ accumulation and illumination. The migration resulted in the formation of shunt paths, which reduced the shunt resistance and open circuit voltage. Furthermore, ingression of water into the ZnO:Al is expected to be responsible for a slow but steady increase in series resistance for both high and low alkali solar cells. Additionally, sodium migration led to a severe increase of the series resistance in case of alkali rich samples. Copyright © 2015 John Wiley & Sons, Ltd.     

SARS-CoV-2 Spike Protein and Mouse Coronavirus Inhibit Biofilm Formation by Streptococcus pneumoniae and Staphylococcus aureus

The presence of co-infections or superinfections with bacterial pathogens in COVID-19 patients is associated with poor outcomes, including increased morbidity and mortality. We hypothesized that SARS-CoV-2 and its components interact with the biofilms generated by commensal bacteria, which may contribute to co-infections. This study employed crystal violet staining and particle-tracking microrheology to characterize the formation of biofilms by Streptococcus pneumoniae and Staphylococcus aureus that commonly cause secondary bacterial pneumonia. Microrheology analyses suggested that these biofilms were inhomogeneous soft solids, consistent with their dynamic characteristics. Biofilm formation by both bacteria was significantly inhibited by co-incubation with recombinant SARS-CoV-2 spike S1 subunit and both S1 + S2 subunits, but not with S2 extracellular domain nor nucleocapsid protein. Addition of spike S1 and S2 antibodies to spike protein could partially restore bacterial biofilm production. Furthermore, biofilm formation in vitro was also compromised by live murine hepatitis virus, a related beta-coronavirus. Supporting data from LC-MS-based proteomics of spike–biofilm interactions revealed differential expression of proteins involved in quorum sensing and biofilm maturation, such as the AI-2E family transporter and LuxS, a key enzyme for AI-2 biosynthesis. Our findings suggest that these opportunistic pathogens may egress from biofilms to resume a more virulent planktonic lifestyle during coronavirus infections. The dispersion of pathogens from biofilms may culminate in potentially severe secondary infections with poor prognosis. Further detailed investigations are warranted to establish bacterial biofilms as risk factors for secondary pneumonia in COVID-19 patients.     

Cell-Based Chemical Safety Assessment and Therapeutic Discovery Using Array-Based Sensors

Synthetic chemicals are widely used in food, agriculture, and medicine, making chemical safety assessments necessary for environmental exposure. In addition, the rapid determination of chemical drug efficacy and safety is a key step in therapeutic discoveries. Cell-based screening methods are non-invasive as compared with animal studies. Cellular phenotypic changes can also provide more sensitive indicators of chemical effects than conventional cell viability. Array-based cell sensors can be engineered to maximize sensitivity to changes in cell phenotypes, lowering the threshold for detecting cellular responses under external stimuli. Overall, array-based sensing can provide a robust strategy for both cell-based chemical risk assessments and therapeutics discovery.     

Mining the Wheat Grain Proteome

Bread wheat is the most widely cultivated crop worldwide, used in the production of food products and a feed source for animals. Selection tools that can be applied early in the breeding cycle are needed to accelerate genetic gain for increased wheat production while maintaining or improving grain quality if demand from human population growth is to be fulfilled. Proteomics screening assays of wheat flour can assist breeders to select the best performing breeding lines and discard the worst lines. In this study, we optimised a robust LC–MS shotgun quantitative proteomics method to screen thousands of wheat genotypes. Using 6 cultivars and 4 replicates, we tested 3 resuspension ratios (50, 25, and 17 µL/mg), 2 extraction buffers (with urea or guanidine-hydrochloride), 3 sets of proteases (chymotrypsin, Glu-C, and trypsin/Lys-C), and multiple LC settings. Protein identifications by LC–MS/MS were used to select the best parameters. A total 8738 wheat proteins were identified. The best method was validated on an independent set of 96 cultivars and peptides quantities were normalised using sample weights, an internal standard, and quality controls. Data mining tools found particularly useful to explore the flour proteome are presented (UniProt Retrieve/ID mapping tool, KEGG, AgriGO, REVIGO, and Pathway Tools).