Histone deacetylase inhibitors target diabetes via chromatin remodeling or as chemical chaperones?

Globally, obesity and diabetes (particularly type 2 diabetes) represents a major challenge to world health. Despite decades of intense research efforts, the genetic basis involved in diabetes pathogenesis & conditions associated with obesity are still poorly understood. Recent advances have led to exciting new developments implicating epigenetics as an important mechanism underpinning diabetes and obesity related disease. One epigenetic mechanism known as the "histone code" describes the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as lysine acetyltransferases or KATs and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. Some of the known inhibitors of HDACs (HDACi) have also been shown to act as "chemical chaperones" to alleviate diabetic symptoms. In this review, we discuss the available evidence concerning the roles of HDACs in regulating chaperone function and how this may have implications in the management of diabetes. © 2009 Bentham Science Publishers Ltd.

The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule

IRE1 couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of the Xbp1 mRNA and in the regulated degradation of diverse membrane-bound mRNAs. We report on the identification of a small molecule inhibitor that attains its selectivity by forming an unusually stable Schiff base with lysine 907 in the IRE1 endonuclease domain, explained by solvent inaccessibility of the imine bond in the enzyme-inhibitor complex. The inhibitor (abbreviated 4μ8C) blocks substrate access to the active site of IRE1 and selectively inactivates both Xbp1 splicing and IRE1-mediated mRNA degradation. Surprisingly, inhibition of IRE1 endonuclease activity does not sensitize cells to the consequences of acute endoplasmic reticulum stress, but rather interferes with the expansion of secretory capacity. Thus, the chemical reactivity and sterics of a unique residue in the endonuclease active site of IRE1 can be exploited by selective inhibitors to interfere with protein secretion in pathological settings.

Settlement offers on appeal : when might costs be awarded on the indemnity basis?

In Roberts v Prendergast [2013] QCA 89 the respondent had offered to settle the appeal, purporting to make the offer under Chapter 9 Part 5 of the Uniform Civil Procedure Rules 1999 (Qld) (UCPR). Differing views were expressed in the Court of Appeal regarding the impact in the circumstances of the offer to settle, with the majority concluding that the appellant should pay the respondent’s costs on the standard basis.

Toward biomimetic materials in bone regeneration : functional behavior of mesenchymal stem cells on a broad spectrum of extracellular matrix components

Bone defect treatments can be augmented by mesenchymal stem cell (MSC) based therapies. MSC interaction with the extracellular matrix (ECM) of the surrounding tissue regulates their functional behavior. Understanding of these specific regulatory mechanisms is essential for the therapeutic stimulation of MSC in vivo. However, these interactions are presently only partially understood. This study examined in parallel, for the first time, the effects on the functional behavior of MSCs of 13 ECM components from bone, cartilage and hematoma compared to a control protein, and hence draws conclusions for rational biomaterial design. ECM components specifically modulated MSC adhesion, migration, proliferation, and osteogenic differentiation, for example, fibronectin facilitated migration, adhesion, and proliferation, but not osteogenic differentiation, whereas fibrinogen enhanced adhesion and proliferation, but not migration. Subsequently, the integrin expression pattern of MSCs was determined and related to the cell behavior on specific ECM components. Finally, on this basis, peptide sequences are reported for the potential stimulation of MSC functions. Based on the results of this study, ECM component coatings could be designed to specifically guide cell functions.

Inelastic finite element analysis of composite beams on the basis of the plastic hinge approach

This paper emphasizes material nonlinear effects on composite beams with recourse to the plastic hinge method. Numerous combinations of steel and concrete sections form arbitrary composite sections. Secondly, the material properties of composite beams vary remarkably across its section from ductile steel to brittle concrete. Thirdly, concrete is weak in tension, so composite section changes are dependent on load distribution. To this end, the plastic zone approach is convenient for inelastic analysis of composite sections that can evaluate member resistance, including material nonlinearities, by routine numerical integration with respect to every fiber across the composite section. As a result, many researchers usually adopt the plastic zone approach for numerical inelastic analyses of composite structures. On the other hand, the plastic hinge method describes nonlinear material behaviour of an overall composite section integrally. Consequently, proper section properties for use in plastic hinge spring stiffness are required to represent the material behaviour across the arbitrary whole composite section. In view of numerical efficiency and convergence, the plastic hinge method is superior to the plastic zone method. Therefore, based on the plastic hinge approach, how to incorporate the material nonlinearities of the arbitrary composite section into the plastic hinge stiffness formulation becomes a prime objective of the present paper. The partial shear connection in this paper is by virtue of the effective flexural rigidity as AISC 1993 [American Institute of Steel Construction (AISC). Load and resistance factor design specifications. 2nd ed., Chicago; 1993]. Nonlinear behaviour of different kinds of composite beam is investigated in this paper, including two simply supported composite beams, a cantilever and a two span continuous composite beam.

Identifying Core Functions of Asset Management

It is widely acknowledged that effective asset management requires an interdisciplinary approach, in which synergies should exist between traditional disciplines such as: accounting, engineering, finance, humanities, logistics, and information systems technologies. Asset management is also an important, yet complex business practice. Business process modelling is proposed as an approach to manage the complexity of asset management through the modelling of asset management processes. A sound foundation for the systematic application and analysis of business process modelling in asset management is, however, yet to be developed. Fundamentally, a business process consists of activities (termed functions), events/states, and control flow logic. As both events/states and control flow logic are somewhat dependent on the functions themselves, it is a logical step to first identify the functions within a process. This research addresses the current gap in knowledge by developing a method to identify functions common to various industry types (termed core functions). This lays the foundation to extract such functions, so as to identify both commonalities and variation points in asset management processes. This method describes the use of a manual text mining and a taxonomy approach. An example is presented.

On Chinese Modal Particle A (啊) : A Pragmatic and Semantic Study

Chinese modal particles feature prominently in Chinese people’s daily use of the language, but their pragmatic and semantic functions are elusive as commonly recognised by Chinese linguists and teachers of Chinese as a foreign language. This book originates from an extensive and intensive empirical study of the Chinese modal particle a (啊), one of the most frequently used modal particles in Mandarin Chinese. In order to capture all the uses and the underlying meanings of the particle, the author transcribed the first 20 episodes, about 20 hours in length, of the popular Chinese TV drama series Kewang ‘Expectations’, which yielded a corpus data of more than 142’000 Chinese characters with a total of 1829 instances of the particle all used in meaningful communicative situations. Within its context of use, every single occurrence of the particle was analysed in terms of its pragmatic and semantic contributions to the hosting utterance. Upon this basis the core meanings were identified which were seen as constituting the modal nature of the particle.

Distinguishing between mechanisms of cell aggregation using pair-correlation functions

Many cell types form clumps or aggregates when cultured in vitro through a variety of mechanisms including rapid cell proliferation, chemotaxis, or direct cell-to-cell contact. In this paper we develop an agent-based model to explore the formation of aggregates in cultures where cells are initially distributed uniformly, at random, on a two-dimensional substrate. Our model includes unbiased random cell motion, together with two mechanisms which can produce cell aggregates: (i) rapid cell proliferation, and (ii) a biased cell motility mechanism where cells can sense other cells within a finite range, and will tend to move towards areas with higher numbers of cells. We then introduce a pair-correlation function which allows us to quantify aspects of the spatial patterns produced by our agent-based model. In particular, these pair-correlation functions are able to detect differences between domains populated uniformly at random (i.e. at the exclusion complete spatial randomness (ECSR) state) and those where the proliferation and biased motion rules have been employed - even when such differences are not obvious to the naked eye. The pair-correlation function can also detect the emergence of a characteristic inter-aggregate distance which occurs when the biased motion mechanism is dominant, and is not observed when cell proliferation is the main mechanism of aggregate formation. This suggests that applying the pair-correlation function to experimental images of cell aggregates may provide information about the mechanism associated with observed aggregates. As a proof of concept, we perform such analysis for images of cancer cell aggregates, which are known to be associated with rapid proliferation. The results of our analysis are consistent with the predictions of the proliferation-based simulations, which supports the potential usefulness of pair correlation functions for providing insight into the mechanisms of aggregate formation.

Media and information literacy : policy and strategy guidelines

In the evolving knowledge societies of today, some people are overloaded with information, others are starved for information. Everywhere, people are yearning to freely express themselves,to actively participate in governance processes and cultural exchanges. Universally, there is a deep thirst to understand the complex world around us. Media and Information Literacy (MIL) is a basis for enhancing access to information and knowledge, freedom of expression, and quality education. It describes skills, and attitudes that are needed to value the functions of media and other information providers, including those on the Internet, in societies and to find, evaluate and produce information and media content; in other words, it covers the competencies that are vital for people to be effectively engaged in all aspects of development.

An improved chemically inducible gene switch that functions in the monocotyledonous plant sugar cane

Chemically inducible gene switches can provide precise control over gene expression, enabling more specific analyses of gene function and expanding the plant biotechnology toolkit beyond traditional constitutive expression systems. The alc gene expression system is one of the most promising chemically inducible gene switches in plants because of its potential in both fundamental research and commercial biotechnology applications. However, there are no published reports demonstrating that this versatile gene switch is functional in transgenic monocotyledonous plants, which include some of the most important agricultural crops. We found that the original alc gene switch was ineffective in the monocotyledonous plant sugar cane, and describe a modified alc system that is functional in this globally significant crop. A promoter consisting of tandem copies of the ethanol receptor inverted repeat binding site, in combination with a minimal promoter sequence, was sufficient to give enhanced sensitivity and significantly higher levels of ethanol inducible gene expression. A longer CaMV 35S minimal promoter than was used in the original alc gene switch also substantially improved ethanol inducibility. Treating the roots with ethanol effectively induced the modified alc system in sugar cane leaves and stem, while an aerial spray was relatively ineffective. The extension of this chemically inducible gene expression system to sugar cane opens the door to new opportunities for basic research and crop biotechnology.

Functional encryption for threshold functions (or fuzzy IBE) from lattices

Cryptosystems based on the hardness of lattice problems have recently acquired much importance due to their average-case to worst-case equivalence, their conjectured resistance to quantum cryptanalysis, their ease of implementation and increasing practicality, and, lately, their promising potential as a platform for constructing advanced functionalities. In this work, we construct “Fuzzy” Identity Based Encryption from the hardness of the Learning With Errors (LWE) problem. We note that for our parameters, the underlying lattice problems (such as gapSVP or SIVP) are assumed to be hard to approximate within supexponential factors for adversaries running in subexponential time. We give CPA and CCA secure variants of our construction, for small and large universes of attributes. All our constructions are secure against selective-identity attacks in the standard model. Our construction is made possible by observing certain special properties that secret sharing schemes need to satisfy in order to be useful for Fuzzy IBE. We also discuss some obstacles towards realizing lattice-based attribute-based encryption (ABE).

Lattice basis delegation in fixed dimension and shorter-ciphertext hierarchical IBE

We present a technique for delegating a short lattice basis that has the advantage of keeping the lattice dimension unchanged upon delegation. Building on this result, we construct two new hierarchical identity-based encryption (HIBE) schemes, with and without random oracles. The resulting systems are very different from earlier lattice-based HIBEs and in some cases result in shorter ciphertexts and private keys. We prove security from classic lattice hardness assumptions.

Shrinking the keys of discrete-log-type lossy trapdoor functions

To this day, realizations in the standard-model of (lossy) trapdoor functions from discrete-log-type assumptions require large public key sizes, e.g., about Θ(λ 2) group elements for a reduction from the decisional Diffie-Hellman assumption (where λ is a security parameter). We propose two realizations of lossy trapdoor functions that achieve public key size of only Θ(λ) group elements in bilinear groups, with a reduction from the decisional Bilinear Diffie-Hellman assumption. Our first construction achieves this result at the expense of a long common reference string of Θ(λ 2) elements, albeit reusable in multiple LTDF instantiations. Our second scheme also achieves public keys of size Θ(λ), entirely in the standard model and in particular without any reference string, at the cost of a slightly more involved construction. The main technical novelty, developed for the second scheme, is a compact encoding technique for generating compressed representations of certain sequences of group elements for the public parameters.

Möbius transforms, coincident Boolean functions and non-coincidence property of Boolean functions

Boolean functions and their Möbius transforms are involved in logical calculation, digital communications, coding theory and modern cryptography. So far, little is known about the relations of Boolean functions and their Möbius transforms. This work is composed of three parts. In the first part, we present relations between a Boolean function and its Möbius transform so as to convert the truth table/algebraic normal form (ANF) to the ANF/truth table of a function in different conditions. In the second part, we focus on the special case when a Boolean function is identical to its Möbius transform. We call such functions coincident. In the third part, we generalize the concept of coincident functions and indicate that any Boolean function has the coincidence property even it is not coincident.

Tandem B1 SINE retro-elements may provide a basis for natural antisense transcription in the Magi1 locus of the mouse (Mus musculus)

Transposable elements, which are DNA sequences that can move between different sites in genomes, comprise approximately 40% of the genome of mammals and are emerging as important contributors to biological diversity. Here we report a transcription unit lying within intron 1 of the murine Magi1 (membrane associated guanylate kinase inverted 1) gene that codes for a cell-cell junction scaffolding protein. The transcription unit, termed Magi1OS (Magi1 Opposite Strand), originates from a region with tandem B1 short interspersed nuclear elements (SINEs) and is an antisense gene to Magi1. Mag1OS transcription initiates in a proximal B1 element that shows only 4% divergence from the consensus sequence, indicating that it has been recently inserted into the mouse genome and could be replication competent. Moreover, a chimaeric transcript may result from intra-chromosomal interaction and trans-splicing of the Magi1 antisense transcript (Magi1OS) and Ghrl, which codes for the multifunctional peptide hormone ghrelin. These two genes are 20 megabases apart on chromosome 6 and are transcribed in opposite directions. We propose that the Magi1OS locus may serve as a useful model system to study exaptation and retrotransposition of B1 SINEs, as well as to examine the mechanisms of intra-chromosomal trans-splicing.