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Abstract: The enzyme NAD(P)H quinone oxidoreductase (NQO1) can function both as a detoxifying enzyme as well as chaperone protein. The latter property has been extensively characterized by the use of dicoumarol which inhibits the chaperone properties of NQO1 in cells. However, the use of this compound is compromised by its multiple “off-target” effects. Coumarin-based compounds that are more potent than dicoumarol as inhibitors of NQO1 in cells have been identified (Nolan et al., Biochem Pharmacol 2010;80:977–81). The purpose of the work reported here is to evaluate the off-target effects of these compounds when compared to dicoumarol. A range of these substituted coumarins are identified that are significantly less toxic than dicoumarol in a panel of nine cell lines. Further a number of the compounds generate much less intracellular superoxide, and many of them also show a reduced ability to induce apoptosis when compared to dicoumarol. None of these effects correlate with the ability of the compounds to inhibit the enzymatic activity of NQO1 in cells. In conclusion, potent inhibitors of NQO1 have been identified that will be more pharmacologically useful than dicoumarol for probing the function of NQO1 in cells and tissues. [ABSTRACT FROM AUTHOR]

Abstract: NAD(P)H quinone oxidoreductase (NQO1) has multiple functions in the cell including an ability to act as a detoxifying enzyme and as a protein chaperone. The latter property is particularly important in oncology as one of the client proteins of NQO1 is p53. The inhibitor, dicoumarol, is classically used to probe the biological properties of NQO1, but interpretation of enzyme function is compromised by the multiple “off-target” effects of this agent. Coumarin-based compounds that are more potent than dicoumarol as inhibitors of recombinant human NQO1 have been identified (Nolan et al., J Med Chem 2009;52:7142–56) The purpose of the work reported here is to demonstrate the functional activity of these agents for inhibiting NQO1 in cells. To do this, advantage was taken of the NQO1-mediated toxicity of the chemotherapeutic drug EO9 (Apaziquone). The toxicity of this drug is substantially reduced when the function of NQO1 is inhibited and many of the coumarin-based compounds are more efficient than dicoumarol for inhibiting EO9 toxicity. The ability to do this appears to be related to their capacity to inhibit NQO1 in cell free systems. In conclusion, agents have been identified that may be more pharmacologically useful than dicoumarol for probing the function of NQO1 in cells and tissues. [ABSTRACT FROM AUTHOR]

Abstract: As technologies evolve, there have been high demands for the three-dimensional (3D) shape measurement techniques to posses the following combined technical features: high accuracy, fast speed, easy implementation, capability of measuring multiple objects as well as measuring complex shapes. Generally, the existing techniques can satisfy some of the requirements, but not all of them. This paper presents four practical considerations in fringe projection profilometry (FPP) based 3D shape measurements, along with simple but robust solutions, including gamma correction of digital projection, arbitrary setup of system components, phase unwrapping with multi-frequency fringes, and system calibration with a least-squares inverse approach. The validity and practicability of the FPP-based 3D shape measurement technique using the four corresponding technical approaches have been verified by experiments. The presented technique is capable of satisfying the various critical demands in enormous scientific and engineering applications. [Copyright &y& Elsevier]

Abstract: Titanium alloy (Ti–6Al–4V) is one of the materials extensively used in the aerospace industry due to its excellent properties of high specific strength and corrosion resistance, but it also presents problems wherein it is an extremely difficult material to machine. The cost associated with titanium machining is also high due to lower cutting speeds (<60m/min) and shorter tool life. Laser-assisted machining (LAM) and consequently hybrid machining is utilized to improve the tool life and the material removal rate. The effectiveness of the two processes is studied by varying the tool material and material removal temperature while measuring the cutting forces, specific cutting energy, surface roughness, microstructure and tool wear. Laser-assisted machining improved the machinability of titanium from low (60m/min) to medium-high (107m/min) cutting speeds; while hybrid machining improved the machinability from low to high (150–200m/min) cutting speeds. The optimum material removal temperature was established as 250°C. Two to three fold tool life improvement over conventional machining is achieved for hybrid machining up to cutting speeds of 200m/min with a TiAlN coated carbide cutting tool. Tool wear predictions based on 3-D FEM simulation show good agreement with experimental tool wear measurements. Post-machining microstructure and microhardness profiles showed no change from pre-machining conditions. An economic analysis, based on estimated tooling and labor costs, shows that LAM and the hybrid machining process with a TiAlN coated tool can yield an overall cost savings of ∼30% and ∼40%, respectively. [Copyright &y& Elsevier]

Abstract: A range of triazoloacridin-6-ones functionalized at C5 and C8 have been synthesized and evaluated for ability to inhibit NQO1 and NQO2. The compounds were computationally docked into the active site of NQO1 and NQO2, and calculated binding affinities were compared with IC50 values for enzyme inhibition. Excellent correlation coefficients were demonstrated suggesting a predictive QSAR model for this series of structurally similar analogues. From this we have identified some of these triazoloacridin-6-ones to be the most potent NQO2 inhibitors so far reported. [Copyright &y& Elsevier]

As a non-beam-based additive manufacturing (AM) method, binder jet 3D printing (BJ3DP) is a process in which a liquid binder is jetted on layers of powdered materials, selectively joined, and then followed by densification process. Among AM technologies, binder jetting holds distinctive promise because of the possibility of rapid production of complex structures to achieve isotropic properties in the 3D printed samples. By taking advantage of traditional powder metallurgy, BJ3DP machines can produce prototypes in which material properties and surface finish are similar to those attained with traditional powder metallurgy. Various powdered materials have been 3D printed, but a typical challenge during BJ3DP is developing printing and post-processing methods that maximize part performance. Therefore, a detailed review of the physical processes during 3D printing and the fundamental science of densification after sintering and post–heat treatment steps are provided to understand the microstructural evolution and properties of binder jetted parts. Furthermore, to determine the effects of the binder jetting process on metallurgical properties, the role of powder characteristics (e.g., morphology, mean size, distribution), printing process parameters (e.g., layer thickness, print orientation, binder saturation, print speed, drying time), sintering (e.g., temperature, holding time), and post-processing are discussed. With the development of AM technologies and the need for post-processing in 3D printed parts, understanding the microstructural evolution during densification is necessary and here, processing steps are explained. Finally, opportunities for future advancement are addressed. [ABSTRACT FROM AUTHOR]

CLLBC(Ce) and TLYC(Ce) are novel scintillation materials capable of measuring mixed gamma ray and neutron radiation fields that have gained significant interest in the areas of space and nuclear safety/security science. To date Geant4, the world's most popular Monte Carlo radiation modelling toolkit, has yet to be effectively used to simulate the full response of these materials when coupled to near ultra-violet Silicon PhotoMultipliers (SiPMs). In this work an experimentally validated Geant4 application has been developed with optimised material composition, optical data tables, and physics transport settings that is able to accurately simulate the response of CLLBC(Ce) and TLYC(Ce) SiPM-based radiation detectors under both gamma ray and neutron irradiation. Experimental benchmarking for five different radioactive sources (Co-60, Cs-137, Eu-152, Am-241, and Cf-252) illustrated that this developed Geant4 application was able to reproduce the position and structure of all major spectral features (full energy gamma ray photo-/neutron capture peaks, X-ray escape photopeaks, Compton edge, Compton backscatter peaks, and Compton plateau) to high level of accuracy. [ABSTRACT FROM AUTHOR]

• This is the first investigated human case of avian influenza A(H9N2) virus infection in Oman, presenting in a 14-month-old female. • This single case raises the question of other possible mild unrecognized infections, especially among high-risk groups such as poultry workers. • This single case re-emphasizes the urgent need for increased efforts to tackle the threat of avian influenza A(H9N2) virus infection by adapting a multisector One Health approach. Following the detection of the first human case of avian influenza A subtype H9N2 in 1998, more than 40 cases were diagnosed worldwide. However, the spread of the virus has been more remarkable and significant in global poultry populations, causing notable economic losses despite its low pathogenicity. Many surveillance studies and activities conducted in several countries have shown the predominance of this virus subtype. We present the case of a 14-month-old female in Oman with an A(H9N2) virus infection. This is the first human case of A(H9N2) reported from Oman and the Gulf Cooperation Countries, and Oman is the second country outside of southern and eastern Asia to report a case (cases have also been detected in Egypt). The patient had bronchial asthma and presented with a high-grade temperature and symptoms of lower respiratory tract infection that necessitated admission to a high dependency unit in a tertiary care hospital. It is of urgency that a multisector One Health approach be established to combat the threat of avian influenza at the animal–human interface. In addition to enhancements of surveillance and control in poultry, there is a need to develop screening and preventive programs for high-risk occupations. [ABSTRACT FROM AUTHOR]

• Influenza virus genomes were extracted from ferret respiratory samples. • Five extraction methods were evaluated by next generation sequencing of viral genomes. • DNase treatment was critical for amplification and sequencing of RNA virus genome. • These findings can be applied to respiratory samples containing other RNA viruses. Influenza A virus is a negative-sense RNA virus with a segmented genome consisting of eight RNA segments. Avian influenza A virus (AIV) primarily infects avian hosts and sporadically infects mammals, which can lead to adaptation to new species. Next-generation sequencing (NGS) of emerging AIV genomes extracted from respiratory samples collected on sequential days from animal models and clinical patients enables analysis of the emergence of evolutionary variants within the virus population over time. However, obtaining codon complete AIV genome at a sufficient coverage depth for nucleotide variant calling remains a challenge, especially from post-inoculation respiratory samples collected at late time points that have low viral titers. In this study, nasal wash samples from ferrets inoculated with different subtypes of AIV were collected on various days post-inoculation. Each nasal wash sample was aliquoted and extracted using five commercially available nucleic acid extraction methods. Extracted influenza virus RNA was amplified and NGS conducted using Illumina Mi-Seq. For each nasal wash sample, completeness of AIV genome segments and coverage depth were compared among five extraction methods. Nucleic acids extracted by MagNA pure compact RNA isolation consistently yielded codon complete sequences for all eight genome segments at the required coverage depth at each time point sampled. The study revealed that DNase treatment was critical to the amplification of influenza genome segments and the downstream success of codon complete NGS from nasal wash samples. The findings from this study can be applied to improve NGS of influenza and other RNA viruses that infect the respiratory tract and are collected from respiratory samples. [ABSTRACT FROM AUTHOR]

Mixing layer height (MLH) is a key parameter for evaluating the transport and diffusion of atmospheric pollutants in both air quality forecasting and satellite data retrieval. However, there is a lack of methods for obtaining the nocturnal MLH. In this study, a novel instrument named the charge-coupled device-laser aerosol detection system (CCD-LADS) was developed to study the nocturnal MLH and boundary layer structure from the surface. The system mainly includes a continuous laser and a charge-coupled device camera with a fisheye lens. Structures of atmospheric layers characterized by the CCD-LADS were compared with those measured by a ceilometer. The heights of two atmospheric layers quantified by measurements with the CCD-LADS and the ceilometer show good agreement, with a relative difference of 5%. The results of this comparison demonstrated that the CCD-LADS is capable of distinctly identifying the nocturnal vertical structure of the atmosphere. The advantage of the CCD-LADS in retrieving the nocturnal MLH is that the CCD-LADS can provide the boundary layer structures under 100 m, while the ceilometer and other lidar measurements cannot retrieve the atmospheric structures below that altitude. CCD-LADS was deployed in a comprehensive field campaign measuring air pollution in the University of Chinese Academy of Sciences, located at the border between the North China Plain and Yanshan Mountain, during January 2016. The fine characteristics and patterns of the nocturnal boundary layer structures were derived with the CCD-LADS measurements. [ABSTRACT FROM AUTHOR]

Summary Background Antiviral drugs are a proposed medical intervention to reduce household transmission of influenza viruses. In a previously described randomised, placebo-controlled trial in Dhaka, Bangladesh, we showed that oseltamivir treatment of index patients was able to reduce influenza symptom duration and virus shedding. In a further analysis that is part of the same study, we aimed to assess efficacy of oseltamivir to reduce secondary household illnesses in the same cohort. Methods In this double-blind oseltamivir efficacy trial, we identified index patients aged older than 1 year through surveillance of households in Dhaka, Bangladesh. We randomly allocated eligible patients (1:1) to receive oseltamivir or placebo twice-daily for 5 days, and we stratified them by enrolment 48 h versus 48–120 h since illness onset. Participants provided nasal wash specimens at enrolment and 2, 4, and 7 days after enrolment and were visited daily by a research assistant to record symptoms, both in index patients and in household members. For this part of the study, household members were asked to give respiratory specimens for influenza PCR testing. Our primary outcomes were household secondary illness and PCR-confirmed influenza virus infection, assessed in household members of all randomly allocated index patients. This trial is registered with ClinicalTrials.gov , number NCT00707941 . Findings From May 11, 2008, to Dec 31, 2010, we enrolled 1190 index patients with 4694 household members. 592 patients were allocated to placebo (2292 household members) and 598 to oseltamivir (2402 household members). Household secondary illness was lower in the oseltamivir group (196 [8%] influenza cases) than in the placebo group (233 [10%]; odds ratio [OR] 0·77, 95% CI 0·60–0·98, p=0·031). PCR-confirmed influenza virus infection did not differ between the placebo (103 [5%]) and oseltamivir groups (92 [4%]; 0·84, 0·59–1·19, p=0·319); however, only 243 (57%) of ill household members gave a specimen for analysis. Interpretation In a crowded, low income setting, oseltamivir treatment of index patients resulted in a small reduction of secondary influenza in their households. Even this slight reduction, in the setting of widespread antiviral use during a community influenza outbreak, might result in reductions in overall disease burden. Funding Centers for Disease Control and Prevention (in an agreement with the International Centre for Diarrhoeal Disease Research, Bangladesh). [ABSTRACT FROM AUTHOR]

Highlights: [•] Sensitive and strain-specific rRT-PCR assays were developed for each gene segment of influenza viruses used to prepare live attenuated influenza vaccine (LAIV) reassortant viruses. [•] rRT-PCR assays proved to be adequate and sufficient to provide the evidence for the homogeneity of the LAIV reassortant viruses. [•] Complete genome sequencing of all viruses confirmed the stability of the LAIV reassortant genome. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of benz[h]isoquinolines has been achieved using a highly convergent photochemical method. The approach presented provides ready access to biologically active compounds and building blocks not readily available through other methods. [Copyright &y& Elsevier]

Baloxavir, a new antiviral drug targeting cap-dependent endonuclease activity of polymerase acidic (PA) protein of influenza viruses, is now approved in multiple countries. Several substitutions at isoleucine 38 in PA protein (e.g., PA-I38T) have been associated with decreased baloxavir susceptibility in vitro and in vivo. In recent years, next generation sequencing (NGS) analysis and pyrosequencing have been used by CDC and U.S. Public Health Laboratories to monitor drug susceptibility of influenza viruses. Here we described an improved pyrosequencing assay for detecting influenza A viruses carrying substitutions at PA-38. Cyclic and customized orders of nucleotide dispensation were evaluated, and pyrosequencing results were compared to those generated using NGS. Our data showed that the customized nucleotide dispensation has improved the pyrosequencing assay performance in identification of double mixtures (e.g., PA-38I/T); however, identification of PA-38 variants in triple mixtures remains a challenge. While NGS analysis indicated the presence of PA-I38K in one clinical specimen and isolate, our attempts to detect this mutation by pyrosequencing or recover the virus carrying PA-I38K in cell culture were unsuccessful, raising a possibility of a rarely occurring sequencing error. Overall, pyrosequencing provides a convenient means to detect baloxavir resistant influenza viruses when NGS is unavailable or a faster turnaround time is required. • Pyrosequencing assay was optimized to improve detection of baloxavir resistant influenza A viruses in mixtures. • Detection of PA-38 variants in virus mixtures of both subtypes was improved by using customized nucleotide dispensation. • Pyrosequencing and NGS data were comparable, except for lysine at PA-38 that was detected by NGS but not by pyrosequencing. • Attempts to recover virus carrying lysine at PA-38 were unsuccessful, raising the rare possibility of an NGS artifact. • Pyrosequencing provides an important addition to genotypic methods that can be used for baloxavir susceptibility testing. [ABSTRACT FROM AUTHOR]