Advancements in the Development of non-BET Bromodomain Chemical Probes

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high-quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non-BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non-BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non-BET bromodomains as tractable therapeutic targets.     

Advanced intelligent networks: now a reality

This paper looks first at the background to the development of intelligent networking concepts and then tracks this development to the advanced intelligent networks (AINs) of today. The network architecture and basic nodal functions are explained, and a brief review given of the essential intelligent network building blocks, namely the IN (intelligent network) call model and the enhanced CCITT No.7 signalling system. Typical intelligent network services are examined and the tutorial finishes with a review of the latest IN standards     

Finite element computation of electromagnetic fields [hyperthermiatreatment]

A three dimensional finite element solution scheme is developed for numerically computing electromagnetically induced power depositions. The solution method is applicable to those problems for which it can be reasonably assumed that the magnetic permeability is homogeneous. The method employs an incident field/scattered field approach where the incident field is precalculated and used as the forcing function for the computation of the scattered field. A physically logical condition is used for the numerical boundary conditions to overcome the fact that electromagnetic problems are generally unbounded (i.e., the boundary condition is applied at infinity) but numerical models must have a boundary condition applied to some finite location. At that numerical boundary, an outgoing spherical wave is simulated. Finally, an alternate to a direct solution scheme is described. This alternate method, a preconditioned conjugate gradient solver, provides both a storage and CPU time advantage over direct solution methods. For example, a one-thousand fold decrease in CPU time was achieved for simple test cases. Unlike most iterative methods, the preconditioned conjugate gradient technique used has the important property of guaranteed convergence. Solutions obtained from this finite element method are compared to analytic solutions demonstrating that the solution method is second-order accurate     

A new model of job design: Initial evidence and implications for future research

Clegg and Spencer's (2007) model of job design synthesizes and extends recent conceptions of the job design process by incorporating variables such as knowledge, motivation, and trust into a cyclical and dynamic system. The objective of this study was to examine the sequential organization of variables that comprise the model, as a basis from which to justify further investigations of the model's dynamic properties. Data were collected via questionnaires from 432 participants in two work organizations. Results obtained from structural equation modeling are broadly supportive of the proposed relationships between the variables. Implications of this initial study for future research and practice are discussed. © 2011 Wiley Periodicals, Inc.     

Appropriate technology for manufacturing: Some management issues

This paper introduces the idea of appropriate technology and applies it to the choices organisations make when designing, implementing and managing advanced manufacturing technologies. Five sets of choices are considered: the type and level of technology; the allocation of functions between humans and machines; the role of humans in advanced systems; the organisation structures to support them; and the ways in which people participate in their design. The paper concludes that most organisations are not effective at developing and implementing appropriate technologies, and that ergonomists have failed to meet the needs of technologies and managers in these areas.     

Synthesis and structure of the n = 4 member of the framework aluminium alkylenediphosphonate series Al2[O3PCnH2nPO3](H2O)2F2

We report here the solvothermal synthesis and crystal structure of the hybrid inorganic-organic framework material Al₂[O₃PC₄H₈PO₃](H₂O)₂F₂⋅2H₂O (monoclinic, 1P2₁/m, a = 4.961(2) ?, b = 11.930(5) ?, c = 10.727(5) ?, β = 93.972(6)^∘, Z = 2, R(F, F² > 2σ) = 0.094, R_w(F², all data) = 0.262), the third member of the Al₂[O₃PC_nH_2nPO₃](H₂O)₂F₂ framework series. The structure is formed from corrugated chains of corner-sharing AlO₄F₂ octahedra in which alternating AlO₄F₂ octahedra contain two fluorine atoms in a trans or a cis configuration. The diphosphonate groups link the chains together through Al-O-P-O-Al bridges and through the butyl groups to form a three-dimensional framework structure containing a one-dimensional channel system consisting of one type of channel only. The channels contain four extra-framework water molecules per unit cell. The formation of this member of the series shows that the form of the alkyl chain can successfully define the number of channel types and the channel length in this hybrid framework system.     

Predicting whether a material is ductile or brittle

In this paper we discuss the various models that have been used to predict whether a material will tend to be ductile or brittle. The most widely used is the Pugh ratio, $G/K$, but we also examine the Cauchy pressure as defined by Pettifor, a combined criterion proposed by Niu, the Rice and Thomson model, the Rice model, and the Zhou-Carlsson-Thomson model. We argue that no simple model that works on the basis of simple relations of bulk polycrystalline properties can represent the failure mode of different materials, particularly where geometric effects occur, such as small sample sizes. Instead the processes of flow and fracture must be considered in detail for each material structure, in particular the effects of crystal structure on these processes.     

HLA-DRB1 genes and disease severity in rheumatoid arthritis. The MIRA Trial Group. Minocycline in Rheumatoid Arthritis

OBJECTIVE: To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) trial. METHODS: Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression. RESULTS: At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-treated, but not the minocycline-treated, patients. A treatment group/HLA-DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two-thirds of African-American patients did not have the rheumatoid epitope. CONCLUSION: HLA-DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African-American patients with RA.     

Observations of the preferential loss of major ions from melting snow and laboratory ice

Two types of laboratory experiments were undertaken to understand changes in the ionic composition of solutions from melting snows: (1) a set of field-laboratory experiments which involved partially melting recently collected snows and (2) experiments on the controlled melting of artificial ices of known composition. Sulphate and nitrate ions are preferentially lost with respect to chloride during the melting process so apparent elution sequence may be written SO₄²⁻ > NO₃⁻ > Cl⁻. Of the cations, sodium appears to be removed least readily giving an elution sequence Mg²⁺ = K⁺ > Na⁺. In the laboratory the differences in the efficiency of removal of ions from ice are small in the first stages of melting, but pronounced by the end of the melt. Sodium and chloride are expected to be proportionally enriched in residual leached snow packs. This is generally born out by field observations. The preferential loss of some ions is more evident in aged laboratory ice than in the freshly made ice. The changes in the ice and meltwater composition throughout the process of melting may be understood to arise from the mixing of two types of solutions: (i) an intergranular surficial brine with high solute concentration that occupies the ice grain boundaries and (ii) the meltwater from the ice grains.     

Impacts of environmental product legislation on solid oxide fuel cells

Ongoing development of solid oxide fuel cell (SOFC) technology coincides with a rapid increase in legislation aiming to control the environmental impacts of products across their life cycle. A risk-based method is used to explore the potential future impacts of this body of legislation on the technology. Legislation controlling the use of hazardous materials is one area of significance. Under the new European REACH Regulation some nickel compounds, used widely throughout general industry but also in the fabrication of anode structures, may fall under the classification of a substance of very high concern (SVHC) in future, which presents a risk of restrictions being placed on their continued use. This risk must drive the development of alternative anode materials, or requires the SOFC industry to identify a socio-economic argument justifying exemption from any future restrictions. A legislative trend establishing recycling requirements for end-of-life products is also identified as having a potential future impact on the technology. Recycling strategies for SOFC products must be considered, prior to commercialisation. It is proposed that failure to meet these future environmental requirements may be detrimental to the perception of SOFC technology, the demand for which is substantially driven by the environmental benefits offered over incumbent power generation technologies. The consideration of these issues in the design of commercial products will mitigate this risk.