Binding Networks Identify Targetable Protein Pockets for Mechanism-Based Drug Design

The human genome codes only a few thousand druggable proteins, mainly receptors and enzymes. While this pool of available drug targets is limited, there is an untapped potential for discovering new drug-binding mechanisms and modes. For example, enzymes with long binding cavities offer numerous prerequisite binding sites that may be visited by an inhibitor during migration from a bulk solution to the destination site. Drug design can use these prerequisite sites as new structural targets. However, identifying these ephemeral sites is challenging. Here, we introduce a new method called NetBinder for the systematic identification and classification of prerequisite binding sites at atomic resolution. NetBinder is based on atomistic simulations of the full inhibitor binding process and provides a networking framework on which to select the most important binding modes and uncover the entire binding mechanism, including previously undiscovered events. NetBinder was validated by a study of the binding mechanism of blebbistatin (a potent inhibitor) to myosin 2 (a promising target for cancer chemotherapy). Myosin 2 is a good test enzyme because, like other potential targets, it has a long internal binding cavity that provides blebbistatin with numerous potential prerequisite binding sites. The mechanism proposed by NetBinder of myosin 2 structural changes during blebbistatin binding shows excellent agreement with experimentally determined binding sites and structural changes. While NetBinder was tested on myosin 2, it may easily be adopted to other proteins with long internal cavities, such as G-protein-coupled receptors or ion channels, the most popular current drug targets. NetBinder provides a new paradigm for drug design by a network-based elucidation of binding mechanisms at an atomic resolution.     

Bioavailability Improvement Strategies for Icariin and Its Derivates: A Review

In recent years, there has been considerable interest in icariin (ICA) and its derivates, icariside II (ICS) and icaritin (ICT), due to their wide range of potential applications in preventing cancer, cardiovascular disease, osteoporosis, delaying the effects of Alzheimer’s disease, treating erectile dysfunction, etc. However, their poor water solubility and membrane permeability, resulting in low bioavailability, dampens their potential beneficial effects. In this regard, several strategies have been developed, such as pharmaceutical technologies, structural transformations, and absorption enhancers. All these strategies manage to improve the bioavailability of the above-mentioned flavonoids, thus increasing their concentration in the desired places. This paper focuses on gathering the latest knowledge on strategies to improve bioavailability for enhancing the efficacy of icariin, icariside II, and icaritin. We conclude that there is an opportunity for many further improvements in this field. To the best of our knowledge, no such review articles scoping the bioavailability improvement of icariin and its derivates have been published to date. Therefore, this paper can be a good starting point for all those who want to deepen their understanding of the field.     

Yield estimation and forecasting for winter wheat in Hungary using time series of MODIS data

Wheat is one of the most important crops in Hungary, which represents approximately 20% of the entire agricultural area of the country, and about 40% of cereals. A robust yield method has been improved for estimating and forecasting wheat yield in Hungary in the period of 2003–2015 using normalized difference vegetation index (NDVI) derived from the data of the Moderate Resolution Imaging Spectroradiometer. Estimation was made at the end of June – it is generally the beginning of harvest of winter wheat in Hungary – while the forecasts were performed 1–7 weeks earlier. General yield unified robust reference index (GYURRI) vegetation index was calculated each year using different curve-fitting methods to the NDVI time series. The correlation between GYURRI and country level yield data gave correlation coefficient (r) of 0.985 for the examined 13 years in the case of estimation. Simulating a quasi-operative yield estimation process, 10 years’ (2006–2015) yield data was estimated. The differences between the estimated and actual yield data provided by the Hungarian Central Statistical Office were less than 5%, the average difference was 2.5%. In the case of forecasting, these average differences calculated approximately 2 and 4 weeks before the beginning of harvest season were 4.5% and 6.8%, respectively. We also tested the yield estimation procedure for smaller areas, for the 19 counties (Nomenclature of Territorial Units for Statistics-3 level) of Hungary. We found that, the relationship between GYURRI and the county level yield data had r of 0.894 for the years 2003–2014, and by simulating the quasi-operative forecast for 2015, the resulting 19 county average yield values differed from the actual yield as much as 8.7% in average.     

2D operators on topographic and non‐topographic architectures—implementation,efficiency analysis,and architecture selection methodology

Topographic and non‐topographic image processing architectures and chips, developed within the CNN community recently, are analyzed and compared. It is achieved on a way that the 2D operators are collected to classes according to their implementation methods on the different architectures, and the main implementation parameters of the different operator classes are compared. Based on the results, an efficient architecture selection methodology is formalized. Copyright © 2010 John Wiley & Sons, Ltd.     

Parallel sphere detector algorithm providing optimal MIMO detection on massively parallel architectures

Multiple‐input multiple‐output (MIMO) systems have attracted considerable attention in wireless communications because they offer a significant increase in data throughput and link coverage without additional bandwidth requirement or increased transmit power. The price that has to be paid is the increased complexity of hardware components and algorithms. The sphere detector (SD) algorithm solves the problem of maximum likelihood (ML) detection for MIMO channels by significantly reducing the search space of possible solutions. The main drawback of the SD algorithm is in its sequential nature, consequently, running it on massively parallel architectures (MPAs) is very inefficient. In order to overcome the drawbacks of the SD algorithm, a new parallel sphere detector (PSD) algorithm is proposed. It implements a novel hybrid tree search method, where the algorithm parallelism is assured by the efficient combination of depth‐first search and breadth‐first search algorithms. A path metric‐based parallel sorting is employed at each intermediate stage. The PSD algorithm is able to adjust its memory requirements and extent of parallelism to fit a wide range of parallel architectures. Mapping details for MPAs are proposed by giving the details of thread dependent, highly parallel building blocks of the algorithm. Based on the building blocks proposed, a mapping to general‐purpose graphics processing unit is provided, and its performance is evaluated. In order to achieve high‐throughput, several levels of parallelism are introduced, and different scheduling strategies are considered. Copyright © 2015 John Wiley & Sons, Ltd.     

N-Aminierung von Isochinolinbasen

N-Amination of Isoquinoline Bases 3, 3-Pentamethylene oxaziridine 1 forms an N N-bond with secondary isoquinoline bases 2a – f to give the cyclohexylidene hydrazines 3a – f . In some cases nitrogen elimination yielding indane derivatives 13b, 13e competes with hydrazone formation. The cyclic Schiff'base 14 and the β-carboline derivative 16 can also be aminated.     

Modelling brittle impact failure of disc particles using material point method

Understanding the impact failure of particles made of brittle materials such as glasses, ceramics and rocks is an important issue for many engineering applications. During the impact, a solid particle is turned into a discrete assembly of many fragments through the development of multiple cracks. The finite element method is fundamentally ill-equipped to model this transition. Recently a so-called material point method (MPM) has been used to study a wide range of problems of material and structural failures. In this paper we propose a new material point model for the brittle failure which incorporates a statistical failure criterion. The capability of the method for modelling multiple cracks is demonstrated using disc particles. Three impact failure patterns observed experimentally are captured by the model: Hertzian ring cracks, meridian cracks, and multi-fragment cracks. Detailed stress analysis is carried out to interpret the experimental observations. In particular it is shown that the experimentally observed dependence of a threshold velocity for the initiation of meridian cracks on the particle size can be explained by the proposed model. The material point based scheme requires a relatively modest programming effort and avoids node splitting which makes it very attractive over the traditional finite element method.     

Semantics and pragmatics of Real-Time Maude

At present, designers of real-time systems face a dilemma between expressiveness and automatic verification: if they can specify some aspects of their system in some automaton-based formalism, then automatic verification is possible; but more complex system components may be hard or impossible to express in such decidable formalisms. These more complex components may still be simulated; but there is then little support for their formal analysis. The main goal of Real-Time Maude is to provide a way out of this dilemma, while complementing both decision procedures and simulation tools. Real-Time Maude emphasizes ease and generality of specification, including support for distributed real-time object-based systems. Because of its generality, falling outside of decidable system classes, the formal analyses supported—including symbolic simulation, breadth-first search for failures of safety properties, and model checking of time-bounded temporal logic properties—are in general incomplete (although they are complete for discrete time). These analysis techniques have been shown useful in finding subtle bugs of complex systems, clearly outside the scope of current decision procedures. This paper describes both the semantics of Real-Time Maude specifications, and of the formal analyses supported by the tool. It also explains the tool's pragmatics, both in the use of its features, and in its application to concrete examples.     

Application of probabilistic and fuzzy cognitive approaches in semantic web framework for medical decision support

This study aimed to focus on medical knowledge representation and reasoning using the probabilistic and fuzzy influence processes, implemented in the semantic web, for decision support tasks. Bayesian belief networks (BBNs) and fuzzy cognitive maps (FCMs), as dynamic influence graphs, were applied to handle the task of medical knowledge formalization for decision support. In order to perform reasoning on these knowledge models, a general purpose reasoning engine, EYE, with the necessary plug-ins was developed in the semantic web. The two formal approaches constitute the proposed decision support system (DSS) aiming to recognize the appropriate guidelines of a medical problem, and to propose easily understandable course of actions to guide the practitioners. The urinary tract infection (UTI) problem was selected as the proof-of-concept example to examine the proposed formalization techniques implemented in the semantic web. The medical guidelines for UTI treatment were formalized into BBN and FCM knowledge models. To assess the formal models’ performance, 55 patient cases were extracted from a database and analyzed. The results showed that the suggested approaches formalized medical knowledge efficiently in the semantic web, and gave a front-end decision on antibiotics’ suggestion for UTI.