Search

Background: Aedes aegypti (Ae. aegypti) is the major vector that transmits many diseases including dengue, Zika, and filariasis in tropical and subtropical regions. Due to the growing resistance to chemical-based insecticides, biological control methods have become an emerging direction to control mosquito populations. The sterile insect technique (SIT) deploys high doses of ionizing radiation to sterilize male mosquitoes before the release. The Wolbachia-based population suppression method of the incompatible insect technique (IIT) involves the release of Wolbachia-infected males to sterilize uninfected field females. Due to the lack of perfect sex separation tools, a low percentage of female contamination is detected in the male population. To prevent the unintentional release of these Wolbachia-infected females which might result in population replacement, a low dose of X-ray irradiation is deployed to sterilize any female escapees. However, it remains unclear whether these irradiation-induced male and female sterilizations share common mechanisms. Results: In this work, we set out to define the minimum dose of X-ray radiation required for complete female sterilization in Ae. aegypti (NEA-EHI strain). Further results showed that this minimum dose of X-ray irradiation for female sterilization significantly reduced male fertility. Similar results have been reported previously in several operational trials. By addressing the underlying causes of the sterility, our results showed that male sterility is likely due to chromosomal damage in the germ cells induced by irradiation. In contrast, female sterility appears to differ and is likely initiated by the elimination of the somatic supporting cells, which results in the blockage of the ovariole maturation. Building upon these findings, we identified the minimum dose of X-ray irradiation on the Wolbachia-infected NEA-EHI (wAlbB-SG) strain, which is currently being used in the IIT-SIT field trial. Compared to the uninfected parental strain, a lower irradiation dose could fully sterilize wAlbB-SG females. This suggests that Wolbachia-carrying mosquitoes are more sensitive to irradiation, consistent with a previous report showing that a lower irradiation dose fully sterilized Wolbachia-infected Ae. aegypti females (Brazil and Mexican strains) compared to those uninfected controls. Conclusions: Our findings thus reveal the distinct mechanisms of ionizing X-ray irradiation-induced male or female sterility in Ae. aegypti mosquitoes, which may help the design of X-ray irradiation-based vector control methods. [ABSTRACT FROM AUTHOR]

Background: Chikungunya virus (CHIKV) has reemerged as a major public health concern, causing chikungunya fever with increasing cases and neurological complications. Methods: In the present study, we investigated a low-passage human isolate of the East/ Central/South African (ECSA) lineage of CHIKV strain LK(EH)CH6708, which exhibited a mix of small and large viral plaques. The small and large plaque variants were isolated and designated as CHIKV-SP and CHIKV-BP, respectively. CHIKV-SP and CHIKV-BP were characterized in vitro and in vivo to compare their virus production and virulence. Additionally, whole viral genome analysis and reverse genetics were employed to identify genomic virulence factors. Results: CHIKV-SP demonstrated lower virus production in mammalian cells and attenuated virulence in a murine model. On the other hand, CHIKV-BP induced higher pro-inflammatory cytokine levels, compromised the integrity of the blood–brain barrier, and led to astrocyte infection in mouse brains. Furthermore, the CHIKV-SP variant had limited transmission potential in Aedesalbopictus mosquitoes, likely due to restricted dissemination. Whole viral genome analysis revealed multiple genetic mutations in the CHIKV-SP variant, including a Glycine (G) to Arginine (R) mutation at position 55 in the viral E2 glycoprotein. Reverse genetics experiments confirmed that the E2-G55R mutation alone was sufficient to reduce virus production in vitro and virulence in mice. Conclusions: These findings highlight the attenuating effects of the E2-G55R mutation on CHIKV pathogenicity and neurovirulence and emphasize the importance of monitoring this mutation in natural infections. [ABSTRACT FROM AUTHOR]

Pairwise‐based methods such as the free energy perturbation (FEP) method have been widely deployed to compute the binding free energy differences between two similar host–guest complexes. The calculated pairwise free energy difference is either directly adopted or transformed to absolute binding free energy for molecule rank ordering. We investigated, through both analytic derivations and simulations, how the selection of pairs in the experiment could impact the overall prediction precision. Our studies showed that (1) the estimated absolute binding free energy (ΔG^) derived from calculated pairwise differences (ΔΔG) through weighted least squares fitting is more precise in prediction than the pairwise difference values when the number of pairs is more than the number of ligands and (2) prediction precision is influenced by both the total number of pairs and the specifically selected pairs, the latter being critically important when the number of calculated pairs is limited. Furthermore, we applied optimal experimental design in pair selection and found that the optimally selected pairs can outperform randomly selected pairs in prediction precision. In an illustrative example, we showed that, upon weighing ligand structure similarity into design optimization, the weighted optimal designs are more efficient than the literature reported designs. This work provides a new approach to assess retrospective pairwise‐based prediction results, and a method to design new prospective pairwise‐based experiments for molecular lead optimization. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Predicting how a complex molecule reacts with different reagents, and how to synthesise complex molecules from simpler starting materials, are fundamental to organic chemistry. We show that an attention-based machine translation model – Molecular Transformer – tackles both reaction prediction and retrosynthesis by learning from the same dataset. Reagents, reactants and products are represented as SMILES text strings. For reaction prediction, the model "translates" the SMILES of reactants and reagents to product SMILES, and the converse for retrosynthesis. Moreover, a model trained on publicly available data is able to make accurate predictions on proprietary molecules extracted from pharma electronic lab notebooks, demonstrating generalisability across chemical space. We expect our versatile framework to be broadly applicable to problems such as reaction condition prediction, reagent prediction and yield prediction. [ABSTRACT FROM AUTHOR]

It is of great challenge to predict human brain penetration for substrates of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), 2 major efflux transporters at blood-brain barrier. Thus, a physiologically based pharmacokinetic (PBPK) model with the incorporation of in vitro MDR1 and BCRP transporter function data and transporter protein expression levels has been developed. As such, it is crucial to generate MDR1 and BCRP substrate data with a high fidelity. In this study, 2 widely used human MDR1 cell lines from Borst and National Institutes of Health laboratories were evaluated using rodent brain penetration data, and the study suggested that the MDR1 expressed in Madin-Darby canine kidney (MDCK) cell line from National Institutes of Health laboratory predicted brain penetration better, particularly for compounds with a high passive permeability. In addition, human BCRP-MDCK cell line with 1 μM PSC833, a specific MDR1 inhibitor, demonstrated the ability to identify BCRP substrates without the confounding of endogenous canine Mdr1. Comparison of human BCRP and mouse Bcrp transporter functions revealed that the functional differences of BCRP between the 2 species is minimal. The incorporation of both the validated MDR1 and BCRP assays into our brain PBPK model has significantly improved the prediction for the brain penetration of MDR1 and BCRP substrates across species. [ABSTRACT FROM AUTHOR]

Wood adhesives are mostly synthesized from unsustainable and hazardous petrochemical-based formaldehyde. Recently, an inorganic, sustainable and environmentally friendly aluminophosphate adhesive was developed for fabricating various wood-based panels. In order to increase its competitiveness, this study developed an approach for improving the interfacial adhesion of aluminophosphate. Hence, carboxymethyl cellulose was functionalized using 3-aminopropyl triethoxysilane to alter the chemical structures of the adhesive. Thereafter, a face-centered central composite design based on response surface methodology was employed to generate the optimum production conditions for the improved plywood interfaces. Adhesive concentration and hot-press temperature were seen as the significant factors within tested limits. The most appropriate production variables were suggested with a valid predictive model for such conditions. Also, the reaction mechanisms revealed the successful altering of the aluminophosphate properties with a well-uniform adhesive surface. The results indicate that modified adhesives are more thermally stable. Furthermore, the wet bonding strength of the modified adhesive was improved above the minimum threshold (Chinese type II standard ≥0.70 MPa). Therefore, the sustainable (i.e. continuous availability of CMC) approach adopted in this research could be considered as a viable method for improving the properties of aluminophosphate adhesives. [Display omitted] • An eco-friendly and low-cost aluminophosphate adhesive was developed via functionalized carboxymethyl cellulose. • The reaction mechanism revealed successful functionalization of carboxymethyl cellulose. • The production conditions of the plywood were optimized using response surface methodology. • The fabricated plywood satisfied the basic requirements for Type II plywood. [ABSTRACT FROM AUTHOR]

To reduce the use of formaldehyde wood adhesives, a chemical modification of starch with chitosan was explored to prepare an adhesive film for plywood with good adhesive properties, low price, non-toxic, and convenient sizing. The effect of chitosan content of the adhesive film on the shear strength of plywood was studied. The modification mechanism and bonding mechanism of the film were analyzed by FTIR, XPS, XRD and SEM. The results showed that when the amount of chitosan was 30% of starch dry weight, the dry-wet shear strength of plywood met the requirements of Chinese national class Ⅱ plywood (≧ 0.80 MPa). FTIR and XPS analysis showed that –NH 2 in the chitosan reacted with –COOH on starch and wood surface to form amide bond, which specifies the chitosan's role as a coupling agent. XRD and SEM analysis showed that the addition of chitosan disturbed the otherwise orderly arrangement of a starch structure. The structure of the attained modified film is mostly amorphous. Sizing in the form of a adhesive film solves the disadvantage of difficulty in sizing starch adhesive. Compared with commercial adhesives on the market, this adhesive film has the advantages of low price, wide source of raw materials, non-toxic, and is expected to be a good substitute for formaldehyde adhesives on the market. • Raw starch and modifier chitosan are both sustainable resources. • Chitosan is used as a special coupling agent. • The mechanism is –NH 2 and –COOH condensation reaction. • The method of adhesive film sizing is more convenient and simple. • Adhesive film cost is lower than commercial adhesives. [ABSTRACT FROM AUTHOR]

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. [ABSTRACT FROM AUTHOR]