Enthalpy- versus Entropy-Driven Molecular Recognition in the Era of Biologics

Our laboratory has recently identified two nanobodies (small antibodies produced by camelids)—Nb1 and Nb6—that bind efficiently to epithelial growth factor (EGF) and inhibit its ability to activate its receptor (EGFR). Because of the relevance of the EGF/EGFR axis as a target in oncology, these new nanobodies have promising therapeutic potential. This article, however, is focused on another feature of these nanobodies: their distinct thermodynamic signatures. Nb1 binds to EGF through an entropy-driven mechanism whereas Nb6 binds to this factor under enthalpic control. We discuss the advantages and disadvantages of each mechanism in the contexts of traditional medical chemistry (small-molecule drugs) and also of biological drugs. In this latter case, the implications in terms of selectivity are far from being clearly established and further experimental data are required. Their monomeric natures, high stability, and ease of recombinant production make nanobodies ideally suited for thermodynamic studies. Moreover, nanobodies, thanks to their simpler structures in comparison with conventional antibodies, might provide better understanding of the structural basis of the thermodynamic parameters of antigen recognition.     

Pseudouridine synthase 7 impacts Candida albicans rRNA processing and morphological plasticity

RNA can be modified in over 100 distinct ways, and these modifications are critical for function. Pseudouridine synthases catalyse pseudouridylation, one of the most prevalent RNA modifications. Pseudouridine synthase 7 modifies a variety of substrates in Saccharomyces cerevisiae including tRNA, rRNA, snRNA, and mRNA, but the substrates for other budding yeast Pus7 homologues are not known. We used CRISPR-mediated genome editing to disrupt Candida albicans PUS7 and find absence leads to defects in rRNA processing and a decrease in cell surface hydrophobicity. Furthermore, C. albicans Pus7 absence causes temperature sensitivity, defects in filamentation, altered sensitivity to antifungal drugs, and decreased virulence in a wax moth model. In addition, we find C. albicans Pus7 modifies tRNA residues, but does not modify a number of other S. cerevisiae Pus7 substrates. Our data suggests C. albicans Pus7 is important for fungal vigour and may play distinct biological roles than those ascribed to S. cerevisiae Pus7.     

Long-term performance predictions in ground improvements with vacuum assisted Prefabricated Vertical Drains

Investigation into time dependent long-term performance of Prefabricated Vertical Drains (PVDs) combined with vacuum consolidation in thick deposits of clay has been extremely limited. Predicting both settlements and excess pore pressures in such cases has become increasingly challenging when time duration is long-term, e.g. several years. In discussing such matter, finding a suitable model to predict the long-term performance is inevitable. Elasto-plastic analysis models such as Cam-Clay cannot predict long-term time-dependent deformational behaviour in soft soils. In this technical note, a Biot type fully-coupled creep-based elastic viscoplastic (EVP) finite element (FE) numerical model has been extended for application in vacuum consolidation. The vacuum consolidation section of the embankment constructed in Ballina, New South Wales, Australia (hereafter referred as Ballina embankment), is analysed using the model through a unit cell analysis and the numerical predictions are compared with field performance monitoring data up to 1200 days (>3 years). The proposed analysis method for PVD combined with vacuum consolidation involving an EVP model is found to be capable of predicting both short-term and long-term deformational behaviours. Predictions are improved when an exponential function is used for the secondary compression index in the EVP model. Comparison has also been carried out at another location in the embankment where the foundation clay thickness was different to check the precision of the methodology and for better understanding of ground settlement behaviour. Details of the analysis methodology and its validation against field performance data are presented in this note.     

煤粉炉系统在电石渣制水泥生产线的应用

我公司2×3?000 t/d水泥生产线采用100%电石渣替代石灰石配料生产水泥熟料，一线于2010年9月投产，使用化工厂湿法生产乙炔产生的电石渣，湿电石渣水分大（30%左右），易黏结。窑尾收尘器采用电收尘器，收尘器进口温度为100~250 ℃。随着新的环保标准的实施，电收尘器处理后的烟气中粉尘含量达不到新的环保标准要求，后对原有窑尾收尘系统加以改造，改造成电袋复合收尘器。     

Variant of a Solution of an Inverse Problem in the Linear Dynamics of Adsorption

Protection of Metals and Physical Chemistry of Surfaces - The form of elution curves in the linear frontal dynamics of adsorption is studied based on the exact solution of a direct problem. It is...     

Covalently Assembled Dipeptide Nanoparticles with Adjustable Fluorescence Emission for Multicolor Bioimaging

Peptide self-assembly, inspired by the naturally occurring fabrication principle, remains the most attractive in constructing fluorescent nanoagents towards bioimaging. However, the noncovalent interactions that drive peptide self-assembly are usually susceptible to the complex physiological environment; thus leading to disassembly and dysfunction of fluorescent nanoagents. Herein, a covalently crosslinked assembly strategy for fabrication of stable peptide-based nanoparticles with adjustable emission is introduced. In the process of cationic diphenylalanine peptide (H-Phe-Phe-NH₂ ⋅ HCl) self-assembly, glutaraldehyde is used as a crosslinker and the resulting product of the Schiff base reaction can be fluorescent. More importantly, the emission wavelength can be readily tuned by controlling the covalent reaction time. It has been demonstrated that the nanoparticles are stable, even after intracellular uptake, and can be used for sustainable multicolor fluorescent imaging. The strategy with integrating peptide self-assembly and covalent crosslinking could be promising for the design and engineering of functional fluorescent nanoparticles with robust physiological stability and adjustable emission towards improved bioimaging applications.     

Azaaurones as Potent Antimycobacterial Agents Active against MDR- and XDR-TB

Herein we report the screening of a small library of aurones and their isosteric counterparts, azaaurones and N-acetylazaaurones, against Mycobacterium tuberculosis. Aurones were found to be inactive at 20 μm , whereas azaaurones and N-acetylazaaurones emerged as the most potent compounds, with nine derivatives displaying MIC₉₉ values ranging from 0.4 to 2.0 μm . In addition, several N-acetylazaaurones were found to be active against multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical M. tuberculosis isolates. The antimycobacterial mechanism of action of these compounds remains to be determined; however, a preliminary mechanistic study confirmed that they do not inhibit the mycobacterial cytochrome bc1 complex. Additionally, microsomal metabolic stability and metabolite identification studies revealed that N-acetylazaaurones are deacetylated to their azaaurone counterparts. Overall, these results demonstrate that azaaurones and their N-acetyl counterparts represent a new entry in the toolbox of chemotypes capable of inhibiting M. tuberculosis growth.     

Bioactive Membrane Based on Modified Porous Glass

The results of studying the structural parameters and strength characteristics of a bioactive membrane are presented. The membrane was obtained based on high-silica glass via modification with silicon polyoxomolybdate. The membrane strength characteristics were simulated under conditions of the maximum pressure of a vacuum water-jet pump of 300 kPa.     

Influence of iron doping towards the physicochemical and biological characteristics of hydroxyapatite

Hydroxyapatite (HAP) is the naturally occurring mineral form of calcium apatite and the most studied material as a bone substituent. Considering HAP's inherent properties, this study explored changes in HAP's characteristics from doping with other metals such as Fe. To form pure HAP and Fe-HAP with different amounts of Fe, we used the hydrothermal approach, and the composites that formed were thoroughly analyzed for their crystallinity, surface bonding, morphology, magnetic behavior, mechanical strength, biocompatibility, hemocompatibility, and in vitro cytotoxicity. The powder XRD studies confirmed the samples' crystallinity, and the lowest crystalline size was 19.7 nm in 10Fe-HAP. The FTIR analysis confirmed the formation of HAP by the hydroxyl, phosphate, and carbonate groups. The FESEM demonstrated that the morphology of the pure HAP was rod-shaped, which transformed into spheres after Fe doping. The EDS analysis confirmed the successful formation of HAP and Fe-HAP composites. The magnetic studies indicated the diamagnetic behavior of the pure HAP, while the Fe-doped HAPs had a superparamagnetic nature with saturation magnetizations (M_s) of 2Fe-HAP, 4Fe-HAP, and 10Fe-HAP at 0.0062, 0.0092, and 0.029 emu/g respectively. Assessment of the mechanical properties, biocompatibility, hemocompatibility, and cytotoxicity indicated that the Fe-doped HAPs were superior to the pure HAP, and among the Fe-HAPs, the 10Fe-HAP) had the highest amount of Fe and the best characteristics. The studies also indicated that Ca²⁺ interactions influenced the cells via HAP doping with that of Fe, equally increasing the physicochemical and biological properties.