Structure–Activity Relationship Studies on (R)‐PFI‐2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7

SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs. To date, few selective small‐molecule inhibitors have been reported that target SETD7, the most potent being (R)‐PFI‐2. Herein we report structure–activity relationship studies on (R)‐PFI‐2 and its analogues. A library of 29 structural analogues of (R)‐PFI‐2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interactions were found to be a salt bridge and a hydrogen bond formed between (R)‐PFI‐2′s NH₂⁺ group and SETD7′s Asp256 and His252 residue, respectively.     

Functional characterisation of mechanical joints to facilitate its selection during the design of open architecture products

New trends in product design require the use of modularity as key feature aimed to improve functional performance and the generation of open architecture products. For mechanical systems, one of the challenges during early design stages of these products involves the proper selection of joining methods among their constructive components. A robust joint selection process must consider product requirements, life cycle analysis and eventual procedures for assembly and disassembly. However, the general approach towards a Design-for-Assembly (DFA)/Design-for-Disassembly (DFD) only considers design, manufacturing and in some cases final disposal stage. Additionally, most of the works found in the literature are merely focused on assembly operations, disregarding economic and environmental benefits from optimising disassembly complexity. Herein, a functional characterisation of mechanical joint methods for the assembly and disassembly activities that take place throughout the product life cycle is proposed, focusing on open architecture products. Additionally, a classification of joining methods, a joint complexity metric valuation and a selection process are proposed for the conceptual design stage. The approach integrates both DFA and DFD principles in a formal methodology. The proposed selection roadmap can be implemented to increase product sustainability positively regarding resources optimisation, operational time and costs in reuse, remanufacturing and recycling tasks.     

A partial equivalence between shared-memory and message-passing in an asynchronous fail-stop distributed environment

This paper presents a schematic algorithm for distributed systems. This schematic algorithm uses a black-box procedure for communication, the output of which must meet two requirements: a global-order requirement and a deadlock-free requirement. This algorithm is valid in any distributed system model that can provide such a communication procedure that complies with these requirements. Two such models exist in an asynchronous fail-stop environment: one in the shared-memory model and one in the message-passing model. The implementation of the block-box procedure in these models enables us to translate existing algorithms between the two models whenever these algorithms are based on the schematic algorithm.We demonstrate this idea in two ways. First, we present a randomized algorithm for the consensus problem in the message-passing model based on the algorithm of Aspnes and Herlihy [AH] in the shared-memory model. This solution is the fastest known randomized algorithm that solves the consensus problem against a strong fail-stop adversary with one-half resiliency. Second, we solve the processor renaming problem in the shared-memory model based on the solution of Attiyaet al. [ABD⁺] in the message-passing model. The existence of the solution to the renaming problem should be contrasted with the impossibility result for the consensus problem in the shared-memory model [CIL], [DDS], [LA].A preliminary version of this paper, Shared-Memory vs. Message-Passing in an Asynchronous Distributed Environment, appeared inProc. 8th ACM Symp. on Principles of Distributed Computing, pp. 307–318, 1989. Part of this work was done while A. Bar-Noy visited the Computer Science Department, Stanford University, Stanford, CA 94305, USA, and his research was supported in part by a Weizmann fellowship, by Contract ONR N00014-88-K-0166, and by a grant of Stanford's Center for Integrated Systems.     

Remote Usability Evaluation: Overview and Case Studies

Traditional laboratory-based usability evaluations have many costs associated with them: financial costs, temporary loss in participant productivity, travel issues. For this reason, many human-computer interaction practitioners cannot conduct as many test iterations as they would like or may fail to secure representative samples, especially as user groups become more global. In recent years, we have begun to use less expensive remote evaluation techniques to complement traditional methods. This article describes some collaborative software that allows remote evaluations, along with the necessary hardware, to reproduce, as closely as possible, traditional evaluation techniques. It also describes the types of activities that lend themselves to this sort of approach and provides tips for conducting these sorts of sessions. Finally, this article provides data that suggest remote techniques are not only effective at improving interface designs, but also produce results comparable to traditional approaches for typical measures.     

Integration of data validation and user interface concerns in a DSL for web applications

Data validation rules constitute the constraints that data input and processing must adhere to in addition to the structural constraints imposed by a data model. Web modeling tools do not make all types of data validation explicit in their models, hampering full code generation and model expressivity. Web application frameworks do not offer a consistent interface for data validation. In this paper, we present a solution for the integration of declarative data validation rules with user interface models in the domain of web applications, unifying syntax, mechanisms for error handling, and semantics of validation checks, and covering value well-formedness, data invariants, input assertions, and action assertions. We have implemented the approach in WebDSL, a domain-specific language for the definition of web applications.     

Static consistency checking of web applications with WebDSL

Modern web application development frameworks provide web application developers with high-level abstractions to improve their productivity. However, their support for static verification of applications is limited. Inconsistencies in an application are often not detected statically, but appear as errors at run-time. The reports about these errors are often obscure and hard to trace back to the source of the inconsistency. A major part of this inadequate consistency checking can be traced back to the lack of linguistic integration of these frameworks. Parts of an application are defined with separate domain-specific languages, which are not checked for consistency with the rest of the application. Examples include regular expressions, query languages and XML-based languages for definition of user interfaces. We give an overview and analysis of typical problems arising in development with frameworks for web application development, with Ruby on Rails, Lift and Seam as representatives.To remedy these problems, in this paper, we argue that domain-specific languages should be designed from the ground up with static verification and cross-aspect consistency checking in mind, providing linguistic integration of domain-specific sub-languages. We show how this approach is applied in the design of WebDSL, a domain-specific language for web applications, by examining how its compiler detects inconsistencies not caught by web frameworks, providing accurate and clear error messages. Furthermore, we show how this consistency analysis can be expressed with a declarative rule-based approach using the Stratego transformation language.     

Detection of microdroplet size and speed using capacitive sensors

Detection of the presence, size and speed of microdroplets in microfluidic devices is presented using commercially available capacitive sensors which make the droplet based microfluidic systems scalable and inexpensive. Cross-contamination between the droplets is eliminated by introducing a passivation layer between the sensing electrodes and droplets. A simple T-junction generator is used to generate droplets in microchannels. Coplanar electrodes are used to form a capacitance through the microfluidic channel. The change in capacitance due to the presence of a droplet in the sensing area is detected and used to determine the size and speed of the droplet. The design of a single pair of electrodes is used to detect the presence of a droplet and the interdigital finger design is used to detect the size and speed of the droplet. An analytical model is developed to predict the detection signal and guide the experimental optimization of the sensor geometry. The measured droplet information is displayed through a Labview interface in real-time. The use of capacitance sensors to monitor droplet sorting at a T-junction is also presented. The discussions in this paper can be generalized to any droplet detection application and can serve as a guideline in sensor selection.     

Comparison of Low Pressure and Medium Pressure UV Lamps for UV/H2O2 Treatment of Natural Waters Containing Micro Pollutants

UV/H₂O₂ advanced oxidation is an effective barrier against organic micro pollutants. Several studies have focused on the degradation of a wide range of pollutants, but regarding the comparison of low-pressure mercury lamps (LP) with medium-pressure mercury lamps (MP) with respect to energy consumption by the UV/H₂O₂ process, little is known so far. Although the absorbance of H₂O₂ at 254 nm is low, the results of this research show that the yield of hydroxyl radical formation (OH_CT) with LP lamps is comparable or higher than with MP lamps. In a water matrix with a background absorbance due to organics and nitrate, H₂O₂ absorbs UV light very effectively at 254 nm. Generally, due to the contribution of direct photolysis, the degradation of pollutants is better with MP-UV/H₂O₂ than with LP-UV/H₂O₂ at the same UV fluence. Therefore, with LP-UV/H₂O₂ micro pollutants are predominantly degraded through reaction with OH radicals. However, due to the much higher efficiency of LP lamps in converting electrical energy to UV-C light, the energy required to achieve 90% degradation (E_EO) of pesticides and pharmaceuticals can be significantly lower with LP-UV/H₂O₂ than with MP-UV/H₂O₂. Results of bench-scale tests show E_EO data of the LP-UV/H₂O₂ process to be 30%–50% lower than for the MP-UV/H₂O₂ process. At these process conditions MS2 phage inactivation was found to be more than 8 logs for both MP-UV/H₂O₂ and LP-UV/H₂O₂.