Modification by Ubiquitin-Like Proteins: Significance in Apoptosis and Autophagy Pathways

Ubiquitin-like proteins (Ubls) confer diverse functions on their target proteins. The modified proteins are involved in various biological processes, including DNA replication, signal transduction, cell cycle control, embryogenesis, cytoskeletal regulation, metabolism, stress response, homeostasis and mRNA processing. Modifiers such as SUMO, ATG12, ISG15, FAT10, URM1, and UFM have been shown to modify proteins thus conferring functions related to programmed cell death, autophagy and regulation of the immune system. Putative modifiers such as Domain With No Name (DWNN) have been identified in recent times but not fully characterized. In this review, we focus on cellular processes involving human Ubls and their targets. We review current progress in targeting these modifiers for drug design strategies.     

Repurposing the Pummerer Rearrangement: Determination of Methionine Sulfoxides in Peptides

The reversible oxidation of methionine residues in proteins has emerged as a biologically important post-translational modification. However, detection and quantitation of methionine sulfoxide in proteins is difficult. Our aim is to develop a method for specifically derivatizing methionine sulfoxide residues. We report a Pummerer rearrangement of methionine sulfoxide treated sequentially with trimethylsilyl chloride and then 2-mercaptoimidazole or pyridine-2-thiol to produce a dithioacetal product. This derivative is stable to standard mass spectrometry conditions, and its formation identified oxidized methionine residues. The scope and requirements of dithioacetal formation are reported for methionine sulfoxide and model substrates. The reaction intermediates have been investigated by computational techniques and by ¹³C NMR spectroscopy. These provide evidence for an α-chlorinated intermediate. The derivatization allows for detection and quantitation of methionine sulfoxide in proteins by mass spectrometry and potentially by immunochemical methods.     

The management of the project-based organization: A personal reflection

In this paper I make a personal reflection on my research and writings in the field of Project Management over the past 30 years. My research has primarily been about the management of the project-based organization. Within that I have researched governance, organizational behaviour, contingency, marketing, success and shareholder value.     

Ambidextrous strategy and execution in entrepreneurial project-oriented organizations: The case of Pagani supercars

This research explores the dynamics underpinning entrepreneurial project-oriented organizations. Specifically, it focuses on how strategy and execution by projects are managed and how ambidexterity – a firm's ability to exploit old certainties while exploring new possibilities – operates as a logic. The empirical findings from an explorative longitudinal research of supercar maker Pagani Automobili in the period 2007–2019, offer an insight of a complex entrepreneurially led project-oriented organization and suggest three integrative mechanisms that describe the ambidextrous management of the interplay within and between strategy and project levels. Additionally, this research recognizes the critical role of projects also in entrepreneurial environments and suggests that the accomplishment of ambidexterity is unique in nature as it is aimed at reconciling the uniqueness of competitive propositions and that of projects within a unique entrepreneurial environment, opening avenues for more theoretical and empirical studies at the intersection of project management and entrepreneurship.     

APPLICATION OF A FRACTIONAL-STEP SCHEME AND FINITE-VOLUME METHOD FOR SIMULATING FLOW PAST A SURFACE-MOUNTED MIXING TAB

The fractional-step scheme and finite-volume method are applied on a structured body-fitted grid to simulate the flow passing over a trapezoidal tab mounted on a flat plate. The implementation of boundary conditions on tab surfaces is greatly simplified with this grid system. Due to grid nonorthogonality, however, discretization of Navier-Stokes equations leads to linear systems with complicated coefficient matrices. For the problem size in this work, performance data indicate that parallel operations occupy about 98.38 % of the simulation, giving rise to a maximum parallel speedup of S p, max , 61.73. The flow passing over the trapezoidal tab is simulated at a Reynolds number Re = 600 based on the inlet free-stream velocity and the tab height, and the results are compared with a particle image velocimetry (PIV) measurement with the same parameters. The simulation successfully captures the vortex structures in the tab wake as observed in the experiments. Comparisons of the instantaneous flow patterns, the mean velocity, and second-order moments also show good agreement. The simulation and PIV experiment also produce a similar shear-stress distribution along the streamwise direction at the flat plate.     

Metal interactions in contaminated freshwater sediments from the fly river floodplain,Papua New Guinea

Field data for sediment pH, Eh, sulphur and organic matter were analysed to determine their relationship with measured dissolved and particulate metals from sites in the Fly River affected by mine‐derived wastes. The above‐background concentrations of dissolved metals correspond to various concentration groups as demonstrated by copper for background (< 70 mg/kg), moderate (70–500mg/kg) and severe (> 500mg/kg), respectively. Dissolved Cu (r = 0.7431, p < 0.0005) and Mo (r = 0.7133,/> < 0.0005) were significantly correlated with their sediment component. Dissolved Al, Cd, Cu and Mo were positively correlated with sediment pH. Significant negative correlation between dissolved copper and sediment (SOM) organic matter (r = ‐0.3821, p < 0.05), and positive correlation with dissolved Al (r = 0.9358, p < 0.0005) suggest that dissolved Cu is present as a complex with either organic matter, Al/Fe oxyhydroxides, or oxyhydroxide‐organic matter colloids. Significant interrelations between dissolved Al, Cu and Mo with organic matter and the ratio of Fe/SOM also suggests that sediment physico‐chemical characteristics are important in the processes occurring in the Fly River floodplain sediments. These processes appear to be responsible for the significantly increased metal concentration in the water column.     

Dynamic delayed detached eddy simulation of a multi‐inlet vortex reactor

The multi‐inlet vortex reactor (MIVR) is used for flash nanoprecipitation to manufacture functional nanoparticles. A validated computational fluid dynamics model is needed for the design, scale‐up, and optimization of the MIVR. Unfortunately, available Reynolds‐averaged Navier‐Stokes methods are unable to accurately model the highly swirling flow in the MIVR. Large‐eddy simulations (LES) are also problematic, as excessively fine grids are required to accurately model this flow. These dilemmas led to the application of the dynamic delayed detached eddy simulation (DDES) method to the MIVR. In the dynamic DDES model, the eddy viscosity has a form similar to the Smagorinsky sub‐grid viscosity in LES, which allows the implementation of a dynamic procedure to determine its model coefficient. Simulation results using the dynamic DDES model are found to match well with experimental data in terms of mean velocity and turbulence intensity, suggesting that the dynamic DDES model is a good option for modeling the turbulent swirling flow in the MIVR. © 2016 American Institute of Chemical Engineers AIChE J, 62: 2570–2578, 2016     

Additive Manufacturing of Dense Ceramic Parts via Direct Ink Writing of Aqueous Alumina Suspensions

Additive manufacturing of near‐net‐shaped dense ceramic components has been established via room‐temperature direct writing of highly loaded aqueous alumina suspensions in a layer‐by‐layer fashion. The effect of alumina solid loading on rheology, specimen uniformity, density, microstructure, and mechanical properties was studied. All suspensions contained a polymer binder (~5 vol.%), dispersant, and 51–58 vol.% alumina powder. Rheological measurements indicated all suspensions to be yield‐pseuodoplastic, and both yield stress and viscosity were found to increase with increasing alumina solid loading. Shear rates ranging from 19.5 to 24.2/s, corresponding to viscosities of 9.8 to 17.2 Pa·s, for the 53–56 vol.% alumina suspensions were found to produce the best results for the 1.25‐mm tip employed during writing. All parts were sintered to >98% of true density, with grain sizes ranging from 3.2 to 3.7 μm. The average flexure strength, which ranged from 134 to 157 MPa, was not influenced by the alumina solid loading.     

On problems without polynomial kernels

Kernelization is a strong and widely-applied technique in parameterized complexity. A kernelization algorithm, or simply a kernel, is a polynomial-time transformation that transforms any given parameterized instance to an equivalent instance of the same problem, with size and parameter bounded by a function of the parameter in the input. A kernel is polynomial if the size and parameter of the output are polynomially-bounded by the parameter of the input.In this paper we develop a framework which allows showing that a wide range of FPT problems do not have polynomial kernels. Our evidence relies on hypothesis made in the classical world (i.e. non-parametric complexity), and revolves around a new type of algorithm for classical decision problems, called a distillation algorithm, which is of independent interest. Using the notion of distillation algorithms, we develop a generic lower-bound engine that allows us to show that a variety of FPT problems, fulfilling certain criteria, cannot have polynomial kernels unless the polynomial hierarchy collapses. These problems include k-Path, k-Cycle, k-Exact Cycle, k-Short Cheap Tour, k-Graph Minor Order Test, k-Cutwidth, k-Search Number, k-Pathwidth, k-Treewidth, k-Branchwidth, and several optimization problems parameterized by treewidth and other structural parameters.