Evidence-based nanoscopic and molecular framework for excipient functionality in compressed orally disintegrating tablets

The work investigates the adhesive/cohesive molecular and physical interactions together with nanoscopic features of commonly used orally disintegrating tablet (ODT) excipients microcrystalline cellulose (MCC) and D-mannitol. This helps to elucidate the underlying physico-chemical and mechanical mechanisms responsible for powder densification and optimum product functionality. Atomic force microscopy (AFM) contact mode analysis was performed to measure nano-adhesion forces and surface energies between excipient-drug particles (6-10 different particles per each pair). Moreover, surface topography images (100 nm2-10 μm2) and roughness data were acquired from AFM tapping mode. AFM data were related to ODT macro/microscopic properties obtained from SEM, FTIR, XRD, thermal analysis using DSC and TGA, disintegration testing, Heckel and tabletability profiles. The study results showed a good association between the adhesive molecular and physical forces of paired particles and the resultant densification mechanisms responsible for mechanical strength of tablets. MCC micro roughness was 3 times that of D-mannitol which explains the high hardness of MCC ODTs due to mechanical interlocking. Hydrogen bonding between MCC particles could not be established from both AFM and FTIR solid state investigation. On the contrary, D-mannitol produced fragile ODTs due to fragmentation of surface crystallites during compression attained from its weak crystal structure. Furthermore, AFM analysis has shown the presence of extensive micro fibril structures inhabiting nano pores which further supports the use of MCC as a disintegrant. Overall, excipients (and model drugs) showed mechanistic behaviour on the nano/micro scale that could be related to the functionality of materials on the macro scale. © 2014 Al-khattawi et al.

The ‘situated functionality’ of accounting in private equity practices:a social ‘site’ analysis

This paper contributes to the recent ‘practice turn’ in management accounting literature in two ways: (1) by investigating the meshing and consequently the ‘situated functionality’ of accounting in various private equity (PE) practices, and (2) by experimenting with the application of Schatzki’s ‘site’ ontology. By identifying and describing the role and nature of accounting and associated calculative practices in different parts of the PE value chain, we note that the ‘situated functionality’ of accounting is ‘prefigured’ by its ‘dispersed’ nature. A particular contribution of experimenting with Schatzki’s ‘site’ ontology has been to identify theoretical concerns in relation to the meaning and role of the concept ‘general understandings’ and to clarify the definitional issues surrounding this concept. We also identify the close relationship between ‘general understandings’ and ‘teleoaffective structure’ and note their mutually constitutive nature.

Personal Work Space and Content Analysis Functionality in a Cultural Heritage Digital Library

The paper presents a different vision for personalization of the user’s stay in a cultural heritage digital library that models services for personalized content marking, commenting and analyzing that doesn’t require strict user profile, but aims at adjusting the user’s individual needs. The solution is borrowed from real work and studying of traditional written content sources (incl. books, manuals), where the user mainly performs activities such as underlining the important parts of the content, writing notes and inferences, selecting and marking zones of their interest in pictures, etc. In the paper a special attention is paid to the ability to execute learning analysis allowing different ways for the user to experience the digital library content with more creative settings.

Modelling the Functionality of the Multimedia Digital Library for Fashion Objects

This paper describes a project of a multimedia digital library for fashion objects. The presented work aims to provide an environment for the National Art Academy students works, showing in front a professional and nonprofessional public the significant values of the fashion domain.

A methodological evaluation and predictive in silico investigation into the multi-functionality of arginine in directly compressed tablets

The acceleration of solid dosage form product development can be facilitated by the inclusion of excipients that exhibit poly-/multi-functionality with reduction of the time invested in multiple excipient optimisations. Because active pharmaceutical ingredients (APIs) and tablet excipients present diverse densification behaviours upon compaction, the involvement of these different powders during compaction makes the compaction process very complicated. The aim of this study was to assess the macrometric characteristics and distribution of surface charges of two powders: indomethacin (IND) and arginine (ARG); and evaluate their impact on the densification properties of the two powders. Response surface modelling (RSM) was employed to predict the effect of two independent variables; Compression pressure (F) and ARG percentage (R) in binary mixtures on the properties of resultant tablets. The study looked at three responses namely; porosity (P), tensile strength (S) and disintegration time (T). Micrometric studies showed that IND had a higher charge density (net charge to mass ratio) when compared to ARG; nonetheless, ARG demonstrated good compaction properties with high plasticity (Y=28.01MPa). Therefore, ARG as filler to IND tablets was associated with better mechanical properties of the tablets (tablet tensile strength (σ) increased from 0.2±0.05N/mm2 to 2.85±0.36N/mm2 upon adding ARG at molar ratio of 8:1 to IND). Moreover, tablets' disintegration time was shortened to reach few seconds in some of the formulations. RSM revealed tablet porosity to be affected by both compression pressure and ARG ratio for IND/ARG physical mixtures (PMs). Conversely, the tensile strength (σ) and disintegration time (T) for the PMs were influenced by the compression pressure, ARG ratio and their interactive term (FR); and a strong correlation was observed between the experimental results and the predicted data for tablet porosity. This work provides clear evidence of the multi-functionality of ARG as filler, binder and disintegrant for directly compressed tablets.

Advanced functionality for radio analysis in the Offline software framework of the Pierre Auger Observatory.

The advent of the Auger Engineering Radio Array (AERA) necessitates the development of a powerful framework for the analysis of radio measurements of cosmic ray air showers. As AERA performs "radio-hybrid" measurements of air shower radio emission in coincidence with the surface particle detectors and fluorescence telescopes of the Pierre Auger Observatory, the radio analysis functionality had to be incorporated in the existing hybrid analysis solutions for fluorescence and surface detector data. This goal has been achieved in a natural way by extending the existing Auger Offline software framework with radio functionality. In this article, we lay out the design, highlights and features of the radio extension implemented in the Auger Offline framework. Its functionality has achieved a high degree of sophistication and offers advanced features such as vectorial reconstruction of the electric field, advanced signal processing algorithms, a transparent and efficient handling of FFTs, a very detailed simulation of detector effects, and the read-in of multiple data formats including data from various radio simulation codes. The source code of this radio functionality can be made available to interested parties on request. (C) 2011 Elsevier B.V. All rights reserved.

A framework for rapid post-earthquake assessment of bridges and restoration of transportation network functionality using structural health monitoring

Peer reviewed

On the mobility, membrane location and functionality of mechanosensitive channels in Escherichia coli

We thank Frans Bianchi and Franz Ho for assistance with molecular cloning, Tim Rasmussen for providing the pTRC-MscK plasmid, Andrew Robinson for providing the pBAD-mEos3.2 plasmid, Matthias Heinemann for assistance with the flow cytometry measurements, Paul Schavemaker for performing Smoldyn simulations and Michiel Punter for programming ImageJ plugins for PALM reconstructions and single-particle tracking. We thank Ian Booth for critical reading of the manuscript, and Christoffer Åberg and Matteo Gabba for valuable discussions. The authors would like to thank David Dryden and Marcel Reuter for performing preliminary experiments from which this work has been built. The work was funded by the EU FP7 ITN-network program NICHE.

Insights into Nonpilus Adhesin Functionality and the Molecular Determinants of Nontypeable Haemophilus influenzae Colonization

Bacterial colonization of the upper respiratory tract is the first step in the pathogenesis of nontypeable Haemophilus influenzae (NTHi) disease. Examination of the determinants of NTHi colonization process has been hampered by the lack of an appropriate animal model. To address this, we have developed a model of NTHi colonization in adult rhesus macaques that involves intranasal inoculation of 1x105 CFU and results in persistent colonization of the upper respiratory tract for at least three weeks with no signs of disease, mimicking asymptomatic colonization of humans. Using this model, we assessed the contributions to colonization of the HMW1 and HMW2 adhesive proteins. In competition experiments, the parent strain expressing both HMW1 and HMW2 was able to efficiently out-compete an isogenic mutant strain expressing neither HMW1 nor HMW2. In experiments involving inoculation of single isogenic derivatives of NTHi strain 12, the strains expressing HMW1 or HMW2 or both were able to colonize efficiently, while the strain expressing neither HMW1 nor HMW2 colonized inefficiently. Furthermore, colonization resulted in antibody production against HMW1 and HMW2 in one-third of the animals, demonstrating that colonization can be an immunizing event. In conclusion, we have established that NTHi is capable of colonizing the upper respiratory tract of rhesus macaques, in some cases associated with stimulation of an immune response. The HMW1 and HMW2 adhesive proteins play a major role in the process of colonization.

After establishing that the HMW1 and HMW2 proteins are colonization factors we further investigated the determinants of HMW1 function. HMW1 is encoded in the same genetic locus as two other proteins, HMW1B and HMW1C, with which HMW1 must interact in order to be functional. Interaction with HMW1C in the cytoplasm results in the glycosylation of HMW1. By employing homologues of HMW1C that glycosylate HMW1 in slightly different patterns we show that the pattern of modification is critical to HMW1 function. Structural analysis showed a change in protein structure when the pattern of HMW1 modification differed. We also identified two specific sites which must be glycosylated for HMW1 to function properly. These point mutations did not have a significant effect on protein structure, suggesting that glycosylation at those specific sites is instead necessary for interaction of HMW1 with its receptor. HMW1B is an outer membrane pore through which HMW1 is transported to reach the bacterial cell surface. We observed that HMW1 isolated from the cytoplasm has a different structure than HMW1 isolated from the bacterial cell surface. By forcing HMW1 to be secreted in a non-HMW1B dependent manner, we show that secretion alone is not sufficient for HMW1 to obtain a functional structure. This leads us to hypothesize that there is something specific in the interaction between HMW1 and HMW1B that aids in proper HMW1 folding.

The NTHi HMW1C glycosyltransferase mediates unconventional N-linked glycosylation of HMW1. In this system, HMW1 is modified in the cytoplasm by sequential transfer of hexose residues. To determine if this mechanism of N-linked glycosylation is employed by species other than NTHi, we examined Kingella kingae and Aggregatibacter aphrophilus homologues of HMW1C. We found both homologues to be functional glycosyltransferases and identified their substrates as the K. kingae Knh and the A. aphrophilus EmaA trimeric autotransporter proteins. LC-MS/MS analysis revealed multiple sites of N-linked glycosylation on Knh and EmaA. Without glycosylation, Knh and EmaA failed to facilitate wild type levels of bacterial autoaggregation or adherence to human epithelial cells, establishing that glycosylation is essential for proper protein function.

Bioengineering of nisin to enhance functionality against dairy pathogens

The bacteriocin class of antimicrobial peptides have emerged as a viable alternative to at least partially fill the void created by the end of the golden age of antibiotic discovery. Along with this potential use in a clinical setting, bacteriocins also play an important role as bio-preservatives in the food industry. This thesis focuses on a specific bacteriocin group, the lantibiotics (Lanthionine-containing antibiotics). Their numerous methods of appliance in a food setting and how their gene-encoded nature can be modified to improve on overall bioactivity and functionality are explored here. The use of a lantibiotic (lacticin 3147) producing starter culture to control the Crohn’s disease-linked pathogen Mycobacterium paratuberculosis was assessed in a raw milk cheese. Although lacticin 3147 production did not effectively control the pathogen, the study provided an impetus to employ a variety of PCR-based mutagenesis techniques with a view to the creation of enhanced lantibiotic derivatives. Through the use of these techniques, a number of enhanced derivatives were generated from the ‘hinge’ region of the nisin peptide. Furthermore, a derivative in which the three hinge amino acids were replaced with three alanines represents the first enhanced derivative of nisin to have been designed through a rational process. This derivative also formed the backbone for the creation of an active, trypsin resistant, variant. Through the employment of further mutagenesis methods a derivative was created with potential use as an oral anti-bacterial in the future. Finally a number of lead nisin derivatives were investigated to assess their anti- Streptococcus agalactiae ability, a mastitis associated pathogen. Also a system was developed to facilitate the large scale production of these candidates, or other nisin derivatives, from dairy substrates.

Evaluating Form and Functionality of Pay-For-Performance Plans: The Relative Incentive and Sorting Effects of Merit Pay, Bonuses, and Long-Term Incentives

Using two-year longitudinal data from a large sample of US employees from a service-related organization, the present study investigates the relative effects of three forms of pay-for-performance plans on employees’ job performance (incentive effects) and voluntary turnover (sorting effects). The study differentiates between three forms of pay: merit pay, individual-based bonuses, and long-term incentives. By definition, these PFP plans have different structural elements that distinguish them from each other (i.e., pay plan form) and different characteristics (functionality), such as the degree to which pay and performance are linked and the size of the rewards, which can vary both within and across plan types. Our results provide evidence that merit raises have larger incentive and sorting effects than bonuses and long-term incentives in multi-PFP plan environments where the three PFP plans are operating simultaneously. Only merit pay has both incentive and sorting effects among the three PFP plans. The implications for the PFP-related theory, as well as for the design and implementation of PFP plans, are discussed.

Making Functionality More General

The definition for the notion of a "function" is not cast in stone, but depends upon what we adopt as types in our language. With partial equivalence relations (pers) as types in a relational language, we show that the functional relations are precisely those satisfying the simple equation f = f o fu o f, where "o" and "u" are respectively the composition and converse operators for relations. This article forms part of "A calculational theory of pers as types".

Enterprise Collaboration Framework for Managing, Advancing and Unifying the Functionality of Multiple Cloud-Based Services with the Help of a Graph API

Part 5: Service Orientation in Collaborative Networks

Hyperlinks in e-books : expanding the functionality of end-notes

With its powerful search engines and billions of published pages, the Worldwide Web has become the ultimate tool to explore the human experience. But, despite the advent of the digital revolution, e-books, at their core, have remained remarkably similar to their printed siblings. This has resulted in a clear dichotomy between two ways of reading: on one side, the multi-dimensional world of the Web; on the other, the linearity of books and e-books. My investigation of the literature indicates that the focus of attempts to merge these two modes of production, and hence of reading, has been the insertion of interactivity into fiction. As I will show in the Literature Review, a clear thrust of research since the early 1990s, and in my opinion the most significant, has concentrated on presenting the reader with choices that affect the plot. This has resulted in interactive stories in which the structure of the narrative can be altered by the reader of experimental fiction. The interest in this area of research is not surprising, as the interaction of readers with the fabric of the narrative provides a fertile ground for exploring, analysing, and discussing issues of plot consistency and continuity. I found in the literature several papers concerned with the effects of hyperlinking on literature, but none about how hyperlinked material and narrative could be integrated without compromising the narrative flow as designed by the author. It led me to think that the researchers had accepted hypertextuality and the linear organisation of fiction as being antithetical, thereby ignoring the possibility of exploiting the first while preserving the second. All the works I consulted were focussed on exploring the possibilities provided to authors (and readers) by hypertext or how hypertext literature affects literary criticism. This was true in earlier works by Landow and Harpold and remained true in later works by Bolter and Grusin. To quote another example, in his book Hypertext 3.0, Landow states: “Most who have speculated on the relation between hypertextuality and fiction concentrate [...] on the effects it will have on linear narrative”, and “hypertext opens major questions about story and plot by apparently doing away with linear organization” (Landow, 2006, pp. 220, 221). In other words, the authors have added narrative elements to Web pages, effectively placing their stories in a subordinate role. By focussing on “opening up” the plots, the researchers have missed the opportunity to maintain the integrity of their stories and use hyperlinked information to provide interactive access to backstory and factual bases. This would represent a missing link between the traditional way of reading, in which the readers have no influence on the path the author has laid out for them, and interactive narrative, in which the readers choose their way across alternatives, thereby, at least to a certain extent, creating their own path. It would be, to continue the metaphor, as if the readers could follow the main path created by the author while being able to get “sidetracked” into exploring hyperlinked material. In Hypertext 3.0, Landow refers to an “Axial structure [of hypertext] characteristic of electronic books and scholarly books with foot-and endnotes” versus a “Network structure of hypertext” (Landow, 2006, p. 70). My research aims at generalising the axial structure and extending it to fiction without losing the linearity at its core. In creative nonfiction, the introduction of places, scenes, and settings, together with characterisation, brings to life the facts without altering them; while much fiction draws on facts to provide a foundation, or narrative elements, for the work. But how can the reader distinguish between facts and representations? For example, to what extent do dialogues and perceptions present what was actually said and thought? Some authors of creative nonfiction use end-notes to provide comments and citations while minimising disruption the flow of the main text, but they are limited in scope and constrained in space. Each reader should be able to enjoy the narrative as if it were a novel but also to explore the facts at the level of detail s/he needs. For this to be possible, end-notes should provide a Web-like way of exploring in more detail what the author has already researched. My research aims to develop ways of integrating narrative prose and hyperlinked documents into a Hyperbook. Its goal is to create a new writing paradigm in which a story incorporates a gateway to detailed information. While creative nonfiction uses the techniques of fictional writing to provide reportage of actual events and fact-based fiction illuminates the affectual dimensions of what happened (e.g., Kate Grenville’s The Secret River and Hilary Mantel’s Wolf Hall), Hyperbooks go one step further and link narrative prose to the details of the events on which the narrative is based or, more in general, to information the reader might find of interest. My dissertation introduces and utilises Hyperbooks to engage in two parallel types of investigation Build knowledge about Italian WWII POWs held in Australia and present it as part of a novella in Hyperbook format. Develop a new piece of technology capable of extending the writing and reading process.

NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets

We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality. NKXΔHD, which lacks the homeodomain completely, could heterodimerize with NKX2-5 wild type and its cofactors, including E26 transformationspecific (ETS) family members, through a tyrosine-rich homophilic interaction domain (YRD). Off-targets of NKX2-5 mutants, but not those of an NKX2-5 YRD mutant, showed overrepresentation of ETS binding sites and were occupied by ETS proteins, as determined by DamID. Analysis of kernel transcription factor and ETS targets show that ETS proteins are highly embedded within the cardiac gene regulatory network. Our study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gainof- function in congenital heart disease.