Two-machine open shop scheduling with secondary criteria

This paper considers two-machine open shop problems with secondary criteria where the primary criterion is the minimization of makespan and the secondary criterion is the minimization of the total flow time, total weighted flow time, or total weighted tardiness time. In view of the strongly NP-hard nature of these problems, two polynomially solvable special cases are given and constructive heuristic algorithms based on insertion techniques are developed. A strongly connected neighborhood structure is derived and used to develop effective iterative heuristic algorithms by incorporating iterative improvement, simulated annealing and multi-start procedures. The proposed insertion and iterative heuristic algorithms are empirically evaluated by solving problem instances with up to 80 jobs.     

In formation: Support for flexibility, mobility, collaboration, and coherence

This paper describes support for flexibility, mobility and collaboration in engaging with, and making sense of, information. Our focus lies on the transitions people make between different, dynamic configurations of digital and physical materials, technologies, people and spaces. The technologies we describe have been developed in partnership with landscape architects over the past two years. We show that appliances and people can come together in a way that creates scope for such transitions, collaboration, and the emergence of new ways of working.     

Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects

The voltage-dependent L-type calcium channel isoform Ca_V1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the Ca_V1.2 α₁-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified Ca_V1.2^L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.     

In Vitro Angiogenesis Inhibition and Endothelial Cell Growth and Morphology

A co-culture assay with human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs) was used to study whether selected angiogenesis inhibitors were able to inhibit differentiation and network formation of HUVECs in vitro. The effect of the inhibitors was determined by the morphology and the calculated percentage area covered by HUVECs. Neutralizing VEGF with avastin and polyclonal goat anti-VEGF antibody and inhibiting VEGFR2 with sorafenib and vatalanib resulted in the formation of HUVEC clusters of variable sizes as a result of inhibited EC differentiation. Furthermore, numerous inhibitors of the VEGF signaling pathways were tested for their effect on the growth and differentiation of HUVECs. The effects of these inhibitors did not reveal a cluster morphology, either individually or when combined to block VEGFR2 downstream pathways. Only the addition of N-methyl-p-bromolevamisole revealed a similar morphology as when targeting VEGF and VEGFR2, meaning it may have an inhibitory influence directly on VEGFR signaling. Additionally, several nuclear receptor ligands and miscellaneous compounds that might affect EC growth and differentiation were tested, but only dexamethasone gave rise to cluster formation similarly to VEGF-neutralizing compounds. These results point to a link between angiogenesis, HUVEC differentiation and glucocorticoid receptor activation.     

Research Validation: Challenges and Opportunities in the Construction Domain

Validation of the research methodology and its results is a fundamental element of the process of scholarly endeavor. Approaches used for construction engineering and management research have included experiments, surveys and observational studies, modeling and simulation, theory building, case studies, and various subtypes thereof. Some studies use more than one approach. A particular contribution of this paper is that it reviews different types of validation using examples of studies, analyzes the specific challenges that were found to be significant, and presents how they were successfully overcome in each case. Another contribution is that it describes new opportunities for research validation that are emerging at the horizon as well as ongoing collaborative efforts to enhance the access of construction researchers to validation tools. This paper increases the awareness of the paramount role that validation techniques play in scholarly work by providing readers with recommendations to properly validate their own research efforts.     

Maxsim2—Real-time interactive simulations for computer-assisted teaching of pharmacokinetics and pharmacodynamics

We developed a computer program for use in undergraduate and graduate courses in pharmacology, pharmacokinetics and pharmacodynamics. This program can also be used in environmental and toxicological studies and preclinical simulation, to facilitate communication between modeling pharmacokineticists and project leaders or other decision-makers in the pharmaceutical industry. The program simulates the drug delivery and transport by means of (I) a six-compartment physiological pharmacokinetic flow model, (II) a system of traditional compartment models, or (III) a target-mediated drug disposition system. The program also can be used to simulate instantaneous equilibria between concentration and pharmacodynamic response, or as temporal delays between concentration and response. The latter is done by means of turnover models (indirect response models). Drug absorption, distribution, and elimination are represented by differential equations, which are described by organ and tissue volumes or other volumes of distribution, blood flows, clearance terms, and tissue-to-blood partition coefficients. The user can control and adjust these parameters by means of a slider in real time. By interactively changing the parameter values and simultaneously displaying the resulting concentration–time and/or response–time profiles, users can understand the major mechanisms that govern the disposition or the pharmacological response of the drug in the organism in real time. Schedule dependence is typically seen in clinical practice with a non-linear concentration–response relationship, and is difficult to communicate except via simulations. Here, we sought to illustrate the potential advantages of this approach in teaching pharmacology, pharmacokinetics, and pharmacodynamics to undergraduate pharmacy-, veterinary-, and medical students or to project teams in drug discovery/development.     

Do Not Convert Emulsions into Dynamites

The emulsion explosives have many advantages compared to dynamites from the safety point of view. However, there is a tendency to develop cartridged emulsions to be more and more dynamite-like. According to our opinion this are steps in the wrong direction. It must be better to develop blasting methods, that are adjusted to the properties of the emulsions.     

Catalytic effects of metals of the iron subgroup on the chlorination of titanium carbide to form nanostructural carbon

The effect of the reaction temperature and the metals of an iron subgroup on the thermo-chemical treatment of titanium carbide with a chlorine gas and their influence on the carbon structure obtained thereby was studied. Different analytical methods such as porosity measurements, X-ray diffraction spectrometry and a high-resolution electron microscopy revealed the catalytic behaviour of the above-mentioned metals, which appeared to support the formation of graphitised carbon at much lower temperatures compared to those needed for the ordinary thermo-chemical chlorination of titanium carbide.