Relative free-energy calculations for scaffold hopping-type transformations with an automated RE-EDS sampling procedure

The calculation of relative free-energy differences between different compounds plays an important role in drug design to identify potent binders for a given protein target. Most rigorous methods based on molecular dynamics simulations estimate the free-energy difference between pairs of ligands. Thus, the comparison of multiple ligands requires the construction of a “state graph”, in which the compounds are connected by alchemical transformations. The computational cost can be optimized by reducing the state graph to a minimal set of transformations. However, this may require individual adaptation of the sampling strategy if a transformation process does not converge in a given simulation time. In contrast, path-free methods like replica-exchange enveloping distribution sampling (RE-EDS) allow the sampling of multiple states within a single simulation without the pre-definition of alchemical transition paths. To optimize sampling and convergence, a set of RE-EDS parameters needs to be estimated in a pre-processing step. Here, we present an automated procedure for this step that determines all required parameters, improving the robustness and ease of use of the methodology. To illustrate the performance, the relative binding free energies are calculated for a series of checkpoint kinase 1 inhibitors containing challenging transformations in ring size, opening/closing, and extension, which reflect changes observed in scaffold hopping. The simulation of such transformations with RE-EDS can be conducted with conventional force fields and, in particular, without soft bond-stretching terms.

Age- and Sex-Related Topological Organization of Human Brain Functional Networks and Their Relationship to Cognition

Age and sex associated with changes in the functional brain network topology and cognition in large population of older adults have been poorly understood. We explored this question further by examining differences in 11 resting-state graph theory measures with respect to age, sex, and their relationships with cognitive performance in 17,127 United Kingdom Biobank participants (mean = 62.83 ± 7.41 years). Age was associated with an overall decrease in the effectiveness of network communication (i.e., integration) and loss of functional specialization (i.e., segregation) of specific brain regions. Sex differences were also observed, with women showing more efficient networks, which were less segregated than in men (FDR adjusted p < 0.05). The age-related changes were also more apparent in men than in women, which suggests that men may be more vulnerable to cognitive decline with age. Interestingly, while network segregation and strength of limbic network were only nominally associated with cognitive performance, the network measures collectively were significantly associated with cognition (FDR adjusted p ≤ 0.002). This may imply that individual measures may be inadequate to capture much of the variance in the neural activity or its output and need further refinement. The complexity of the organization of the functional brain may be shaped by the age and sex of an individual, which ultimately may influence the cognitive performance of older adults. Age and sex stratification may be used to inform clinical neuroscience research to identify older adults at risk of cognitive dysfunction.

Functioning of a technical system with an instantly replenished time reserve, taking into account preventive maintenance

В работе рассматривается функционирование технической системы с мгновенно пополняемым резервом времени с учетом профилактики. Приводится описание функционирования такой системы. При использовании аппарата полумарковских исследований производится построение аналитической модели системы с мгновенно пополняемым резервом времени при учете влияния профилактики на ее производительность. При построении полумарковской модели принимается ограничение на количество профилактик за время восстановления рабочего элемента. Описываются полумарковские состояния исследуемой системы, и приводится граф состояний. Определяются времена пребывания в состояниях системы, вероятности переходов и стационарное распределение вложенной цепи Маркова. Для определения функции распределения времени пребывания системы в подмножестве работоспособных состояний с использованием метода траекторий находятся все траектории переходов системы из этого подмножества в подмножество неработоспособных состояний и вероятности их реализации. Определяются времена пребывания системы в найденных траекториях. На основании теоремы полной вероятности определяются функции распределения времен пребывания системы в подмножествах работоспособных и неработоспособных состояний и коэффициент готовности системы. Приводится пример моделирования исследуемой системы. Проводится сравнение полученных результатов с результатами использования теоремы о среднестационарном времени пребывания системы в подмножестве состояний. The work examines the functioning of a technical system with an instantly replenished reserve of time, taking into account prevention. The description of the functioning of such a system is given. When using the apparatus of semi-Markov studies, an analytical model of the system is constructed with an instantly replenished reserve of time, taking into account the effect of prevention on its performance. When constructing a semi-Markov model, a limitation on the number of preventive measures during the restoration of a working element is adopted. The semi-Markov states of the system under study are described, and the state graph is given. The sojourn times in the states of the system, the transition probabilities, and the stationary distribution of the embedded Markov chain are determined. To determine the distribution function of the time spent by the system in a subset of operable states using the trajectory method, all trajectories of the system's transitions from this subset to the subset of inoperable states and the probability of their realization are found. The residence times of the system in the found trajectories are determined. On the basis of the total probability theorem, the distribution functions of the sojourn times of the system in subsets of the healthy and inoperable states and the system availability factor are determined. The modeling example of th system under study is given. The results obtained are compared with the results of using the theorem on the average stationary sojourn time of the system in a subset of states.

Online Activation and Deactivation of a Petri Net Supervisor

This paper highlights algebraic and mathematical properties in symmetry with Petri nets in order to control automated systems such as flexible workshops, which represent one of the most important examples in industry and for discrete event systems in general. This project deals with the problem of forbidden state transition by using a new application of the theory of regions for supervisory control. In the literature, most control synthesis methods suffer greatly from a cumbersome calculation burden of the Petri net supervisor given the complex exploration of the state graph. Our new methodology lightens the computational load of the Petri net supervisor by choosing specific regions on the reachability graph, on which the control is calculated offline using CPLEX. The determined controller is activated online if the process enters the chosen region, and deactivated otherwise. All our experiments were applied in a flexible workshop implemented in our research laboratory, which was used to engrave selected models on glass blocks of different colors.

A graph-based data quality analysis in distributed telemedicine systems

Telemedicine is one of the most rapidly developing areas of healthcare and it plays an increasing role in modern medicine. As the amount of data and demand for features increase, the data paths are becoming ever-more complex. Owing to this, it is vital in telemedicine to find a proper balance between consistency and availability under any given circumstances. However, making a trade-off can significantly influence the quality of the data. This study seeks to get an in-depth view of the problem by considering a real-world telemedicine use-case and elaborating the formal system specification of the scenario. After evaluating the specification, the constructed state graph is examined using graph coloring and other graph algorithms.

LooPy: interactive program synthesis with control structures

One vision for program synthesis, and specifically for programming by example (PBE), is an interactive programmer's assistant, integrated into the development environment. To make program synthesis practical for interactive use, prior work on Small-Step Live PBE has proposed to limit the scope of synthesis to small code snippets, and enable the users to provide local specifications for those snippets. This paradigm, however, does not work well in the presence of loops. We present LooPy, a synthesizer integrated into a live programming environment, which extends Small-Step Live PBE to work inside loops and scales it up to synthesize larger code snippets, while remaining fast enough for interactive use. To allow users to effectively provide examples at various loop iterations, even when the loop body is incomplete, LooPy makes use of live execution , a technique that leverages the programmer as an oracle to step over incomplete parts of the loop. To enable synthesis of loop bodies at interactive speeds, LooPy introduces Intermediate State Graph , a new data structure, which compactly represents a large space of code snippets composed of multiple assignment statements and conditionals. We evaluate LooPy empirically using benchmarks from competitive programming and previous synthesizers, and show that it can solve a wide variety of synthesis tasks at interactive speeds. We also perform a small qualitative user study which shows that LooPy's block-level specifications are easy for programmers to provide.

Infinite-state graph transformation systems under adverse conditions

We present an approach for modeling adverse conditions by graph transformation systems. To this end, we introduce joint graph transformation systems which involve a system, an interfering environment, and an automaton modeling their interaction. For joint graph transformation systems, we present notions of correctness under adverse conditions. Some instances of correctness are expressible in LTL (linear temporal logic), or in CTL (computation tree logic), respectively. In these cases, verification of joint graph transformation systems is reduced to temporal model checking. To handle infinite state spaces, we incorporate the concept of well-structuredness. We discuss ideas for the verification of joint graph transformation systems using results based on well-structuredness.

Context-aware Adaptive Surgery

Deep Neural Networks (DNNs) have made massive progress in many fields and deploying DNNs on end devices has become an emerging trend to make intelligence closer to users. However, it is challenging to deploy large-scale and computation-intensive DNNs on resource-constrained end devices due to their small size and lightweight. To this end, model partition, which aims to partition DNNs into multiple parts to realize the collaborative computing of multiple devices, has received extensive research attention. To find the optimal partition, most existing approaches need to run from scratch under given resource constraints. However, they ignore that resources of devices (e.g., storage, battery power), and performance requirements (e.g., inference latency), are often continuously changing, making the optimal partition solution change constantly during processing. Therefore, it is very important to reduce the tuning latency of model partition to realize the real-time adaption under the changing processing context. To address these problems, we propose the Context-aware Adaptive Surgery (CAS) framework to actively perceive the changing processing context, and adaptively find the appropriate partition solution in real-time. Specifically, we construct the partition state graph to comprehensively model different partition solutions of DNNs by import context resources. Then "the neighbor effect" is proposed, which provides the heuristic rule for the search process. When the processing context changes, CAS adopts the runtime search algorithm, Graph-based Adaptive DNN Surgery (GADS), to quickly find the appropriate partition that satisfies resource constraints under the guidance of the neighbor effect. The experimental results show that CAS realizes adaptively rapid tuning of the model partition solutions in 10ms scale even for large DNNs (2.25x to 221.7x search time improvement than the state-of-the-art researches), and the total inference latency still keeps the same level with baselines.

Age- and sex-related topological organisation of human brain functional networks and their relationship to cognition

Age and sex have been associated with changes in functional brain network topology, which may in turn affect cognition in older adults. We explored this question further by examining differences in 11 resting-state graph theory measures with respect to age, sex, and their relationships with cognitive performance in 17,127 UK Biobank participants. Age was associated with an overall decrease in the effectiveness of network communication (i.e. integration) and loss of functional specialisation (i.e. segregation) of specific brain regions. Sex differences were also observed, with women showing more efficient networks which were less segregated than in men. Age-related changes were also more apparent in men than women, which suggests that men may be more vulnerable to cognitive decline with age. Interestingly, while network segregation and strength of limbic network were only nominally associated with cognitive performance, the network measures collectively were significantly associated with cognition. This may imply that individual measures may be inadequate to capture much of the variance in neural activity or its output and need further refinement.