The DiPPro Approach: Synthesis,Hydrolysis, and Antiviral Activity of Lipophilic d4T Diphosphate Prodrugs

Bioreversible protection of the β‐phosphate group of nucleoside diphosphates (NDPs) as bis(acyloxybenzyl)phosphate esters is presented. To investigate the structure–activity relationship of these potential NDP prodrugs (DiPPro drugs) a series of DiPPro compounds was synthesized bearing fatty acids of various lengths and d4T as a model nucleoside. For synthesis of the lipophilically modified diphosphate group, preformed phosphoramidites were allowed to react with nucleotides, and the β‐P^III moiety was subsequently oxidized. The chemical and enzymatic stability of these prodrugs was studied in different media such as phosphate buffer (pH 7.3) or CEM cell extracts. In all media, the hydrolysis rate was clearly dependent on the acyl moiety and decreased with increasing alkyl chain length. The compounds showed a markedly lower half‐life in cell extracts than in pH 7.3 phosphate buffer due to the presence of enzyme‐catalyzed cleavage. In all media, the DiPPro compounds released d4T diphosphate (d4TDP) as the main product beside d4TMP. In antiviral assays, the compounds proved to be at least as potent as d4T against HIV‐1 and 2 in wild‐type CEM/0 cells. As a proof of concept, compounds with longer acyl residues showed very good anti‐HIV activities in thymidine‐kinase‐deficient cells (CEM/TK^?), indicating their ability to penetrate cell membranes and the delivery of phosphorylated metabolites.     

The construction productivity debate and the measurement of service qualities

Since the 1960s, researchers have provided short-term and long-term explanations for low productivity growth in the construction industry. In retrospect, the main challenge appears to be the measurement of changes in heterogeneous input and output qualities. The aim here is to review earlier construction productivity research and to compare it with more recent approaches to quality measurement used when analysing services productivity, ultimately intending to provide guidance for using performance data from construction projects. Relying on the EU KLEMS database, industries with similar patterns of productivity growth are identified, primarily the business services industry. In services productivity analyses, the attempts to introduce output quality measures reflecting customer satisfaction are particularly interesting, as this creates a link to productivity effects on clients. A conclusion is that it should be possible to use the increasing volume of performance indicator data collected for construction project benchmarking for extending the range of output quality variables. However, resource constraints imply that it is infeasible to base industry productivity statistics on project level data reflecting customer satisfaction and customer productivity effects.     

Evaluation on Snow Infiltration into Heating Ventilation and Air Conditioning Intake： A Numerical Study

A HVAC （heating ventilating and air conditioning） system is generally designed to ventilate an indoor space. In windy and snowy climates dispersed snow particles in ambient air can enter the intake duct, potentially causing a serious problem. The study addresses the influence of suction volumetric flow rates, the potential discrepancy of snow intake based upon the wind direction in relation to the intake vent, and the possible difference in amounts of infiltrated snow particles in varying intake vent design and locations. The necessary characteristic quantities are defined. The simulation results show the rate of infiltration and the efficiency of the chosen intake designs. The magnitude and direction of wind influences snow infiltration significantly. The daily amount of infiltrated snow is introduced to be the characteristic measure of the infiltration in design of the HVAC systems.     

Software-programmable digital pre-distortion on new generation FPGAs

In this paper we present a software programmable design flow that facilitates the implementation and integration of efficient digital pre-distortion (DPD) solutions on the leading-edge field programmable gate arrays, combining industry-standard embedded processors and programmable logic fabric into one chip. In addition to software programmability, another key contribution of this design flow is the flexible partitioning of functionality among the hardware and software components, depending on the complexity of the DPD parameter estimation algorithm in use. We have applied processor-specific optimizations to the software implementation and used Vivado high-level synthesis (HLS) tool as the design tool for the programmable logic. Furthermore, we have compared two different techniques for the integration of hardware and software components, where we have chosen the one with better area/latency trade-off. We present a comprehensive study reporting the DPD parameter update times when exploring the partitioning of the functionality among hardware and software. For low-complexity algorithms, we show that a software-only solution is applicable after carrying out the processor-specific software optimizations. For higher-complexity algorithms, we use Vivado HLS to accelerate the time-consuming blocks in the programmable logic, leading to a speed-up factor of up to 7× in the overall algorithm execution time. We present the performance results for two target devices. We also show that our accelerators use only a small portion of the programmable logic fabric on these devices and that a significant reduction of the system’s energy consumption can be obtained by leveraging the FPGA fabric.     

Endotoxins affect diverse biological activity of chitosans in matters of hemocompatibility and cytocompatibility

Chitosan is used in several pharmaceutical and medical applications, owing to its good cytocompatibility and hemocompatibility. However, there are conflicting reports regarding the biological activities of chitosan with some studies reporting anti-inflammatory properties while others report pro-inflammatory properties. In this regards we analyzed the endotoxin content in five different chitosans and examined these chitosans with their different deacetylation degrees for their hemocompatibility and cytocompatibility. Therefore, we incubated primary human endothelial cells or whole blood with different chitosan concentrations and studied the protein and mRNA expression of different inflammatory markers or cytokines. Our data indicate a correlation of the endotoxin content and cytokine up-regulation in whole blood for Poly-Morpho-Nuclear (PMN)-Elastase, soluble terminal complement complex SC5b-9, complement component C5/C5a, granulocyte colony-stimulating factor, Interleukin-8 (IL), IL-10, IL-13, IL-17E, Il-32α and monocyte chemotactic protein-1. In contrast, the incubation of low endotoxin containing chitosans with primary endothelial cells resulted in increased expression of E-selectin, intercellular adhesion molecule-1, vascular cell adhesion protein-1, IL-1β, IL-6 and IL-8 in endothelial cells. We suggest that the endotoxin content in chitosan plays a major role in the biological activity of chitosan. Therefore, we strongly recommend analysis of the endotoxin concentration in chitosan, before further determining if it has pro- or anti-inflammatory properties or if it is applicable for pharmaceutical and medical fields.     

How do gait frequency and serum-replacement interval affect polyethylene wear in knee-wear simulator tests?

Polyethylene wear (PE) is known to be a limiting factor in total joint replacements. However, a standardized wear test (e.g. ISO standard) can only replicate the complex in vivo loading condition in a simplified form. In this study, two different parameters were analyzed: (a) Bovine serum, as a substitute for synovial fluid, is typically replaced every 500,000 cycles. However, a continuous regeneration takes place in vivo. How does serum-replacement interval affect the wear rate of total knee replacements? (b) Patients with an artificial joint show reduced gait frequencies compared to standardized testing. What is the influence of a reduced frequency? Three knee wear tests were run: (a) reference test (ISO), (b) testing with a shortened lubricant replacement interval, (c) testing with reduced frequency. The wear behavior was determined based on gravimetric measurements and wear particle analysis. The results showed that the reduced test frequency only had a small effect on wear behavior. Testing with 1 Hz frequency is therefore a valid method for wear testing. However, testing with a shortened replacement interval nearly doubled the wear rate. Wear particle analysis revealed only small differences in wear particle size between the different tests. Wear particles were not linearly released within one replacement interval. The ISO standard should be revised to address the marked effects of lubricant replacement interval on wear rate.