A hierarchical approach to multi-project planning under uncertainty

We survey several viewpoints on the management of the planning complexity of multi-project organisations under uncertainty. A positioning framework is proposed to distinguish between different types of project-driven organisations, which is meant to aid project management in the choice between the various existing planning approaches. We discuss the current state of the art of hierarchical planning approaches both for traditional manufacturing and for project environments. We introduce a generic hierarchical project planning and control framework that serves to position planning methods for multi-project planning under uncertainty. We discuss multiple techniques for dealing with the uncertainty inherent to the different hierarchical stages in a multi-project organisation. In the last part of this paper we discuss two cases from practice and we relate these practical cases to the positioning framework that is put forward in the paper

Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-kappa B-mediated inflammation

Activation of inflammatory gene expression is regulated, among other factors, by post-translational modifications of histone proteins. The most investigated type of histone modifications is lysine acetylations. Histone deacetylases (HDACs) remove acetylations from lysines, thereby influencing (inflammatory) gene expression. Intriguingly, apart from histones, HDACs also target non-histone proteins. The nuclear factor kappa B (NF-kappa B) pathway is an important regulator in the expression of numerous inflammatory genes, and acetylation plays a crucial role in regulating its responses. Several studies have shed more light on the role of HDAC 1-3 in inflammation with a particular pro-inflammatory role for HDAC 3. Nevertheless, the HDAC-NF-kappa B interactions in inflammatory signalling have not been fully understood. An important challenge in targeting the regulatory role of HDACs in the NF-kappa B pathway is the development of highly potent small molecules that selectively target HDAC iso-enzymes. This review focuses on the role of HDAC 3 in (NF-kappa B-mediated) inflammation and NF-kappa B lysine acetylation. In addition, we address the application of frequently used small molecule HDAC inhibitors as an approach to attenuate inflammatory responses, and their potential as novel therapeutics. Finally, recent progress and future directions in medicinal chemistry efforts aimed at HDAC 3-selective inhibitors are discussed.</p

The variable effect of polyploidization on the phenotype in Escallonia

To induce new variation within the Escallonia genus, chromosome doubling was performed in E. rubra, E. rosea, and E. illinita, three important species within this genus of mainly evergreen woody ornamental species. Obtained tetraploids and diploid controls were analyzed for rooting capacity, leaf and flower characteristics, and plant architecture using image analysis and cold tolerance. In the present study, a breeders' collection of 23 accessions was characterized cytogenetically and described morphologically. All analyzed species and cultivars were diploid (2n =2x =24), with exception of E. pendula, a tetraploid. Today, breeding in Escallonia is limited to lucky finds in seedling populations and few efforts in interspecific hybridization. Three selected Escallonia species underwent an in vitro chromosome doubling with both oryzalin and trifluralin applied as either a continuous or shock treatment. The treatments successfully induced polyploids in all three species. Image analysis revealed that tetraploid E. rosea had decreased shoot length (from 3.8 to 1.3 cm), higher circularity and more dense growth habit compared to diploids. No significant changes in cold tolerance were seen. Tetraploid E. illinita did not differ in shoot length, but an increased outgrowth of axillary buds on the main axis led to denser plants. For tetraploid E. rubra, an increase in plant height (from 4.9 to 5.5 cm) was observed together with a large decrease in circularity and density due to a more polar outgrowth of branches on the main axis. E. rubra tetraploids bore larger flowers than diploids and had an increased cold tolerance (from 7.7 to 11.8-C). Leaf width and area of tetraploids increased for both E. illinita and E. rubra, while a decrease was seen in E. rosea genotypes. For all three species, the rooting capacity of the tetraploids did not differ from the diploids. We conclude that the effect of polyploidization on Escallonia was highly variable and species dependent

Direction of arrival estimation based on information geometry

In this paper, a new direction of arrival (DOA) estimation approach is devised using concepts from information geometry (IG). The proposed method uses geodesic distances in the statistical manifold of probability distributions parametrized by their covariance matrix to estimate the direction of arrival of several sources. In order to obtain a practical method, the DOA estimation is treated as a single-variable optimization problem, for which the DOA solutions are found by means of a line search. The relation between the proposed method and MVDR beamformer is elucidated. An evaluation of its performance is carried out by means of Monte Carlo simulations and it is shown that the proposed method provides improved resolution capabilities at low SNR with respect to MUSIC and MVDR.Accepted Author ManuscriptCircuits and System

Исследование содержания ионов K⁺, Ca⁺⁺, Na⁺ в крови человека определенных возрастных групп

У статті наведено аналіз методів визначення електролітів у крові, проаналізовано переваги та недоліки цих методів. Головним недоліком є те, що більша частина вимагає для проведення аналізу забір крові у пацієнта. Метод неінвазивного визначення формули крові метаболічних і гемодинамічних показників гомеостазу проводиться без забору крові, але має суттєвий недолік – чутливість теплових датчиків, що розташовують у біологічно активних точках. Незначне зміщення при їх установці призводить до великих помилок вимірювання, що, в свою чергу, спотворює параметри біохімічного аналізу в кінцевому результаті. Обґрунтовано метод вдосконалення функціональної діагностики із застосуванням кардіомоніторингу.In the article is resulted an analysis over the methods of determination of electrolytes is brought in blood, advantages and lacks of these methods are analysed. A main defect is that greater part requires for realization of analysis the fence of blood for a patient. The method of uninvasion determination the formula of blood is metabolic and haemodynamic indexes of homoeostasis is conducted without the fence of blood but has a substantial defect – sensitiveness of thermal sensors which dispose in bioactive points. Little displacement during setting results in the large errors of measuring which in turn will show a wrong biochemical analysis in end-point. A method of perfection of functional diagnostics are offered and reasonable with application in cardiomonitoring.В статье приведен анализ методов определения электролитов в крови, проанализированы преимущества и недостатки этих методов. Главным недостатком является то, что большая часть требует для проведения анализа забор крови у пациента. Метод неинвазивного определения формулы крови метаболических и гемодинамических показателей гомеостаза проводится без забора крови, но имеет существенный недостаток – чувствительность тепловых датчиков, которые располагают в биологически активных точках. Незначительное смещение при установке приводит к большим ошибкам измерения, которое, в свою очередь, будет показывать неправильный биохимический анализ в конечном результате. Обоснован метод совершенствования функциональной диагностики с применением кардиомониторинга

Определение макроэлементов K⁺, Ca⁺⁺, Na⁺ в крови ребенка с последующим оцениванием гомеостаз организма

У статті наведено нові підходи вдосконалення функціональної діагностики із застосуванням кардіомоніторингу. Авторами подано обґрунтування неінвазивного експрес-оцінювання вмісту мікроелементів у крові пацієнта, оцінювання показників гемодинаміки за допомогою математичного моделювання.New approaches of perfection of the system of functional diagnostics with application of cardiomonitoring are produced in the article. The authors suggested mathematically substantiated noninvasive method and device for measurement of indices of gomeostaz.В статье приведены новые подходы совершенствования функциональной диагностики с применением кардиомониторинга. Обоснована разработка неинвазивного оценивания показателей гомеостаза с помощью математической модели

Molecular determinants of avoidance and inhibition of Pseudomonas aeruginosa MexB efflux pump

: Transporters of the resistance-nodulation-cell division (RND) superfamily of proteins are the dominant multidrug efflux power of Gram-negative bacteria. The major RND efflux pump of Pseudomonas aeruginosa is MexAB-OprM, in which the inner membrane transporter MexB is responsible for the recognition and binding of compounds. The high importance of this pump in clinical antibiotic resistance made it a subject of intense investigations and a promising target for the discovery of efflux pump inhibitors. This study is focused on a series of peptidomimetic compounds developed as effective inhibitors of MexAB-OprM. We performed multi-copy molecular dynamics simulations, machine-learning (ML) analyses, and site-directed mutagenesis of MexB to investigate interactions of MexB with representatives of efflux avoiders, substrates, and inhibitors. The analysis of both direct and water-mediated protein-ligand interactions revealed characteristic patterns for each class, highlighting significant differences between them. We found that efflux avoiders poorly interact with the access binding site of MexB, and inhibition engages amino acid residues that are not directly involved in binding and transport of substrates. In agreement, machine-learning models selected different residues predictive of MexB substrates and inhibitors. The differences in interactions were further validated by site-directed mutagenesis. We conclude that the substrate translocation and inhibition pathways of MexB split at the interface (between the main putative binding sites) and at the deep binding pocket and that interactions outside of the hydrophobic patch contribute to the inhibition of MexB. This molecular-level information could help in the rational design of new inhibitors and antibiotics less susceptible to the efflux mechanism. IMPORTANCE Multidrug transporters recognize and expel from cells a broad range of ligands including their own inhibitors. The difference between the substrate translocation and inhibition routes remains unclear. In this study, machine learning and computational and experimental approaches were used to understand dynamics of MexB interactions with its ligands. Our results show that some ligands engage a certain combination of polar and charged residues in MexB binding sites to be effectively expelled into the exit funnel, whereas others engage aromatic and hydrophobic residues that slow down or hinder the next step in the transporter cycle. These findings suggest that all MexB ligands fit into this substrate-inhibitor spectrum depending on their physico-chemical structures and properties

First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors

Genetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a ∼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli