Use of air monitoring and experimental aerosol data for intake assessment for Mayak plutonium workers

One of the major uncertainties in reconstructing doses to Mayak Plutonium (Pu) workers is the unknown exposure patterns experienced by individuals. These uncertainties include the amounts of Pu inhaled, the temporal exposure pattern of Pu air concentration, the particle-size distribution and solubility of the inhaled aerosols. To date, little individual and workplace-specific information has been used to assess these parameters for the Mayak workforce. However, extensive workplace-specific alpha activity air monitoring data set has been collated, which, if coupled with individual occupational histories, can potentially provide customised intake scenarios for individual Mayak workers. The most available Pu air concentration data are annual averages, which exist for over 100 defined work stations at radiochemical and chemical-metallurgical manufacturing facilities and basically for the whole period of Mayak production operations. Much sparser but more accurate data on Pu concentrations in workers' breathing zone are available for some major workplaces and occupations. The latter demonstrate that within a working shift, Pu concentrations varied over a range of several orders of magnitude depending on the nature of the operations performed. An approach to use the collated data set for individual intake reconstruction is formulated and its practical application is demonstrated. Initial results of ongoing experimental study on historic particle size at Mayak PA and their implications for intake estimation are presented.     

Tissue-Specific Downregulation of Fatty Acid Synthase Suppresses Intestinal Adenoma Formation via Coordinated Reprograming of Transcriptome and Metabolism in the Mouse Model of Apc-Driven Colorectal Cancer

Altered lipid metabolism is a potential target for therapeutic intervention in cancer. Overexpression of Fatty Acid Synthase (FASN) correlates with poor prognosis in colorectal cancer (CRC). While multiple studies show that upregulation of lipogenesis is critically important for CRC progression, the contribution of FASN to CRC initiation is poorly understood. We utilize a C57BL/6-Apc/Villin-Cre mouse model with knockout of FASN in intestinal epithelial cells to show that the heterozygous deletion of FASN increases mouse survival and decreases the number of intestinal adenomas. Using RNA-Seq and gene set enrichment analysis, we demonstrate that a decrease in FASN expression is associated with inhibition of pathways involved in cellular proliferation, energy production, and CRC progression. Metabolic and reverse phase protein array analyses demonstrate consistent changes in alteration of metabolic pathways involved in both anabolism and energy production. Downregulation of FASN expression reduces the levels of metabolites within glycolysis and tricarboxylic acid cycle with the most significant reduction in the level of citrate, a master metabolite, which enhances ATP production and fuels anabolic pathways. In summary, we demonstrate the critical importance of FASN during CRC initiation. These findings suggest that targeting FASN is a potential therapeutic approach for early stages of CRC or as a preventive strategy for this disease.     

Upwind-Difference Potentials Method for Patlak-Keller-Segel Chemotaxis Model

We develop a novel upwind-difference potentials method for the Patlak-Keller-Segel chemotaxis model that can be used to approximate problems in complex geometries. The chemotaxis model under consideration is described by a system of two nonlinear PDEs: a convection-diffusion equation for the cell density coupled with a reaction-diffusion equation for the chemoattractant concentration. Chemotaxis is an important process in many medical and biological applications, including bacteria/cell aggregation and pattern formation mechanisms, as well as tumor growth. Furthermore modeling of real biomedical problems often has to deal with the complex structure of computational domains. There is consequently a need for accurate, fast, and computationally efficient numerical methods for different chemotaxis models that can handle arbitrary geometries. The upwind-difference potentials method proposed here handles complex domains with the use of only Cartesian meshes, and can be easily combined with fast Poisson solvers. In the numerical tests presented below we demonstrate the robustness of the proposed scheme.     

Fully Discrete Analysis of a Discontinuous Finite Element Method for the Keller-Segel Chemotaxis Model

This paper formulates and analyzes fully discrete schemes for the two-dimensional Keller-Segel chemotaxis model. The spatial discretization of the model is based on the discontinuous Galerkin methods and the temporal discretization is based either on Forward Euler or the second order explicit total variation diminishing (TVD) Runge-Kutta methods. We consider Cartesian grids and prove fully discrete error estimates for the proposed methods. Our proof is valid for pre-blow-up times since we assume boundedness of the exact solution.     

Degradation of self-assembled monolayers in organic photovoltaic devices

Self-assembled monolayers (SAMs) based on n-octylphosphonic acid (C8PA) and 1H,1H,2H,2H-perfluorooctanephosphonic acid (PFOPA) were investigated for application as an anode buffer layer in C₆₀-based organic photovoltaic (OPV) devices. We found that the degradation of the OPV efficiency with respect to air exposure was significantly reduced with the perfluorinated PFOPA compared to the aliphatic C8PA. We attribute the OPV degradation to moisture diffusion from the top aluminum electrode and the lowering of the anode work function as a result of hydrolysis of the SAM buffer layer.     

Optimized Heterologous Expression and Efficient Purification of a New TRAIL-Based Antitumor Fusion Protein SRH–DR5-B with Dual VEGFR2 and DR5 Receptor Specificity

In the last two decades, bifunctional proteins have been created by genetic and protein engineering methods to increase therapeutic effects in various diseases, including cancer. Unlike conventional small molecule or monotargeted drugs, bifunctional proteins have increased biological activity while maintaining low systemic toxicity. The recombinant anti-cancer cytokine TRAIL has shown a limited therapeutic effect in clinical trials. To enhance the efficacy of TRAIL, we designed the HRH–DR5-B fusion protein based on the DR5-selective mutant variant of TRAIL fused to the anti-angiogenic synthetic peptide HRHTKQRHTALH. Initially low expression of HRH–DR5-B was enhanced by the substitution of E. coli-optimized codons with AT-rich codons in the DNA sequence encoding the first 7 amino acid residues of the HRH peptide. However, the HRH–DR5-B degraded during purification to form two adjacent protein bands on the SDS-PAGE gel. The replacement of His by Ser at position P2 immediately after the initiator Met dramatically minimized degradation, allowing more than 20 mg of protein to be obtained from 200 mL of cell culture. The resulting SRH–DR5-B fusion bound the VEGFR2 and DR5 receptors with high affinity and showed increased cytotoxic activity in 3D multicellular tumor spheroids. SRH–DR5-B can be considered as a promising candidate for therapeutic applications.     

Two-Photon Polymerization of Sugar Responsive 4D Microstructures

Stimuli-responsive hydrogels have attracted much attention owing to the versatility of their programmed response in offering intelligent solutions for biomimicry applications, such as soft robotics, tissue engineering, and drug delivery. To achieve the complexity of biomimetic structures, two photon polymerization (2PP) has provided a means of fabricating intricate 3D structures from stimuli-responsive hydrogels. Rapid swelling hydrogel microstructures are advantageous for osmotically driven stimuli-response, where actuation speed, that is reliant on the diffusion of analytes or bioanalytes, can be optimized. Herein, the flexibility of 2PP is exploited to showcase a novel sugar-responsive, phenylboronic acid-based photoresist. This offers a remarkable solution for achieving fast response hydrogel systems that have been often hindered by the volume-dependent diffusion times of analytes to receptor sites. A phenylboronic acid-based photoresist compatible with 2PP is presented to fabricate stimuli-responsive microstructures with accelerated response times. Moreover, microstructures with programmable actuation (i.e., bending and opening) are fabricated using the same photoresist within a one-step fabrication process. By combining the flexibility of 2PP with an easily adaptable photoresist, an accessible fabrication method is showcased for sophisticated and chemo-responsive 3D hydrogel actuators.