The large-scale penetration of wind power might lead to degradation of the power system stability due to its inherent feature of randomness. Hence, proper control designs which can effectively handle various uncertainties become very crucial. This paper designs a novel robust passive control (RPC) scheme of a doubly-fed induction generator (DFIG) for power system stability enhancement. The combinatorial effect of generator nonlinearities and parameter uncertainties, unmodelled dynamics, wind speed randomness, is aggregated into a perturbation, which is rapidly estimated by a nonlinear extended state observer (ESO) in real-time. Then, the perturbation estimate is fully compensated by a robust passive controller to realize a globally consistent control performance, in which the energy of the closed-loop system is carefully reshaped through output feedback passification, such that a considerable system damping can be injected to improve the transient responses of DFIG in various operation conditions of power systems. Six case studies are carried out while simulation results verify that RPC can rapidly stabilize the disturbed DFIG system much faster with less overshoot, as well as supress power oscillations more effectively compared to that of linear proportional-integral-derivative (PID) control and nonlinear feedback linearization control (FLC). Full article

Routing protocols based on topology control are significantly important for improving network longevity in wireless sensor networks (WSNs). Traditionally, some WSN routing protocols distribute uneven network traffic load to sensor nodes, which is not optimal for improving network longevity. Differently to conventional WSN routing protocols, we propose a dynamic hierarchical protocol based on combinatorial optimization (DHCO) to balance energy consumption of sensor nodes and to improve WSN longevity. For each sensor node, the DHCO algorithm obtains the optimal route by establishing a feasible routing set instead of selecting the cluster head or the next hop node. The process of obtaining the optimal route can be formulated as a combinatorial optimization problem. Specifically, the DHCO algorithm is carried out by the following procedures. It employs a hierarchy-based connection mechanism to construct a hierarchical network structure in which each sensor node is assigned to a special hierarchical subset; it utilizes the combinatorial optimization theory to establish the feasible routing set for each sensor node, and takes advantage of the maximum–minimum criterion to obtain their optimal routes to the base station. Various results of simulation experiments show effectiveness and superiority of the DHCO algorithm in comparison with state-of-the-art WSN routing algorithms, including low-energy adaptive clustering hierarchy (LEACH), hybrid energy-efficient distributed clustering (HEED), genetic protocol-based self-organizing network clustering (GASONeC), and double cost function-based routing (DCFR) algorithms. Full article

AVR1674 and AVR1675 are monoclonal antibodies (mAbs) that bind with high specificity to anthrax toxin lethal factor (LF) and lethal toxin (LTx). These mAbs have been used as pivotal reagents to develop anthrax toxin detection tests using mass spectrometry. The mAbs were demonstrated to bind LF with good affinity (K_D 10⁻⁷–10⁻⁹ M) and to enhance LF-mediated cleavage of synthetic peptide substrates in vitro. Sequence analysis indicated that the mAbs shared 100% amino acid identity in their complementarity determining regions (CDR). A phage display library based on a combinatorial library of random heptapeptides fused to the pIII coat protein of M13 phage was enriched and screened to identify peptide sequences with mAb binding properties. Selection and sequence analysis of 18 anti-LF-reactive phage clones identified a 7-residue (P1–P7) AVR1674/1675 consensus target binding sequence of T_P1-X_P2-K/R_P3-D_P4-D/E_P5-Z_P6-X/Z_P7 (X = aromatic, Z = non-polar). The phage peptide sequence with highest affinity binding to AVR1674/1675 was identified as T-F-K-D-E-I-V. Synthetic oligopeptides were designed based on the phage sequences and interacted with mAbs with high affinity (K_D ~ 10⁻⁹ M). Single amino acid substitutions of A, H, or Q in the peptides identified positions P1–P5 as critical residues for mAb-peptide interactions. CLUSTALW alignment of phage sequences with native LF implicated residues 644–650 (sequence T-H-Q-D-E-I-Y) as a putative linear epitope component located within a structural loop (L2) of LF Domain IV. The activation effects of these mAbs contribute to the analytic sensitivity of function-based LF detection assays. Full article

The no idle permutation flow shop scheduling problem (NIPFSP) is a popular NP-hard combinatorial optimization problem, which exists in several real world production processes. This study proposes a novel hybrid estimation of the distribution algorithm and cuckoo search (CS) algorithm (HEDA_CS) to solve the NIPFSP with the total tardiness criterion minimization. The problem model is built on the basis of the starting and ending time point of each job. A discrete solution representation method is applied in HEDA_CS to increase the operation efficiency. A novel probability matrix build method is also designed within the knowledge of the processing time matrix. The partially-mapped crossover operation works effectively during the CS phase. A suitable knowledge-based local search is also designed in the HEDA_CS to balance the exploitation and exploration. Finally, many simulations based on the new hard Ruiz benchmarks are conducted. Computational results demonstrate the effectiveness of the proposed HEDA_CS. Full article

With cancer often classified as a disease that has an important epigenetic component, natural compounds that have the ability to regulate the epigenome become ideal candidates for study. Humans have a complex diet, which illustrates the need to elucidate the mechanisms of interaction between these bioactive compounds in combination. The natural compounds withaferin A (WA), from the Indian winter cherry, and sulforaphane (SFN), from cruciferous vegetables, have numerous anti-cancer effects and some report their ability to regulate epigenetic processes. Our study is the first to investigate the combinatorial effects of low physiologically achievable concentrations of WA and SFN on breast cancer cell proliferation, histone deacetylase1 (HDAC1) and DNA methyltransferases (DNMTs). No adverse effects were observed on control cells at optimal concentrations. There was synergistic inhibition of cellular viability in MCF-7 cells and a greater induction of apoptosis with the combinatorial approach than with either compound administered alone in both MDA-MB-231 and MCF-7 cells. HDAC expression was down-regulated at multiple levels. Lastly, we determined the combined effects of these bioactive compounds on the pro-apoptotic BAX and anti-apoptotic BCL-2 and found decreases in BCL-2 and increases in BAX. Taken together, our findings demonstrate the ability of low concentrations of combinatorial WA and SFN to promote cancer cell death and regulate key epigenetic modifiers in human breast cancer cells. Full article

Compared with the fixed fusion structure, the flexible fusion structure with mixed fusion methods has better adjustment performance for the complex air task network systems, and it can effectively help the system to achieve the goal under the given constraints. Because of the time-varying situation of the task network system induced by moving nodes and non-cooperative target, and limitations such as communication bandwidth and measurement distance, it is necessary to dynamically adjust the system fusion structure including sensors and fusion methods in a given adjustment period. Aiming at this, this paper studies the design of a flexible fusion algorithm by using an optimization learning technology. The purpose is to dynamically determine the sensors’ numbers and the associated sensors to take part in the centralized and distributed fusion processes, respectively, herein termed sensor subsets selection. Firstly, two system performance indexes are introduced. Especially, the survivability index is presented and defined. Secondly, based on the two indexes and considering other conditions such as communication bandwidth and measurement distance, optimization models for both single target tracking and multi-target tracking are established. Correspondingly, solution steps are given for the two optimization models in detail. Simulation examples are demonstrated to validate the proposed algorithms. Full article

How to reduce the energy consumption of metro trains by optimizing both the timetable and control strategy is a major focus. Due to the complexity and difficulty of the combinatorial operation problem, the commonly-used method to optimize the train operation problem is based on an unchanged dwelling time for all trains at a specific station. Here, we develop a simulation-based method to design an energy-efficient train control strategy under the optimized timetable constraints, which assign the dwelling time margin to the running time. This time margin is caused by dynamically uncertain passenger demands in off-peak hours. Firstly, we formulate a dwelling time calculation model to minimize the passenger boarding and alighting time. Secondly, we design an optimal train control strategy with fixed time and develop a time-based model to describe mass-belt train movement. Finally, based on this simulation module, we present numerical examples based on the real-world operation data from the Beijing metro Line 2, in which the energy consumption of one train can be reduced by 21.9%. These results support the usefulness of the proposed approach. Full article

Modular polyketide synthases (mPKSs) build functionalized polymeric chains, some of which have become blockbuster therapeutics. Organized into repeating clusters (modules) of independently-folding domains, these assembly-line-like megasynthases can be engineered by introducing non-native components. However, poor introduction points and incompatible domain combinations can cause both unintended products and dramatically reduced activity. This limits the engineering and combinatorial potential of mPKSs, precluding access to further potential therapeutics. Different regions on a given mPKS domain determine how it interacts both with its substrate and with other domains. Within the assembly line, these interactions are crucial to the proper ordering of reactions and efficient polyketide construction. Achieving control over these domain functions, through precision engineering at key regions, would greatly expand our catalogue of accessible polyketide products. Canonical mPKS domains, given that they are among the most well-characterized, are excellent candidates for such fine-tuning. The current minireview summarizes recent advances in the mechanistic understanding and subsequent precision engineering of canonical mPKS domains, focusing largely on developments in the past year. Full article

Versatile odor sensors that can discriminate among huge numbers of environmental odorants are desired in many fields, including robotics, environmental monitoring, and food production. However, odor sensors comparable to an animal’s nose have not yet been developed. An animal’s olfactory system recognizes odor clusters with specific molecular properties and uses this combinatorial information in odor discrimination. This suggests that measurement and clustering of odor molecular properties (e.g., polarity, size) using an artificial sensor is a promising approach to odor sensing. Here, adsorbents composed of composite materials with molecular recognition properties were developed for odor sensing. The selectivity of the sensor depends on the adsorbent materials, so specific polymeric materials with particular solubility parameters were chosen to adsorb odorants with various properties. The adsorption properties of the adsorbents could be modified by mixing adsorbent materials. Moreover, a novel molecularly imprinted filtering adsorbent (MIFA), composed of an adsorbent substrate covered with a molecularly imprinted polymer (MIP) layer, was developed to improve the odor molecular recognition ability. The combination of the adsorbent and MIP layer provided a higher specificity toward target molecules. The MIFA thus provides a useful technique for the design and control of adsorbents with adsorption properties specific to particular odor molecules. Full article

Switchgrass (Panicum virgatum) is a perennial crop producing deep roots and thus highly tolerant to soil water deficit conditions. However, seedling establishment in the field is very susceptible to prolonged and periodic drought stress. In this study, a “sandwich” system simulating a gradual water deletion process was developed. Switchgrass seedlings were subjected to a 20-day gradual drought treatment process when soil water tension was increased to 0.05 MPa (moderate drought stress) and leaf physiological properties had expressed significant alteration. Drought-induced changes in leaf proteomes were identified using the isobaric tags for relative and absolute quantitation (iTRAQ) labeling method followed by nano-scale liquid chromatography mass spectrometry (nano-LC-MS/MS) analysis. Additionally, total leaf proteins were processed using a combinatorial library of peptide ligands to enrich for lower abundance proteins. Both total proteins and those enriched samples were analyzed to increase the coverage of the quantitative proteomics analysis. A total of 7006 leaf proteins were identified, and 257 (4% of the leaf proteome) expressed a significant difference (p < 0.05, fold change <0.6 or >1.7) from the non-treated control to drought-treated conditions. These proteins are involved in the regulation of transcription and translation, cell division, cell wall modification, phyto-hormone metabolism and signaling transduction pathways, and metabolic pathways of carbohydrates, amino acids, and fatty acids. A scheme of abscisic acid (ABA)-biosynthesis and ABA responsive signal transduction pathway was reconstructed using these drought-induced significant proteins, showing systemic regulation at protein level to deploy the respective mechanism. Results from this study, in addition to revealing molecular responses to drought stress, provide a large number of proteins (candidate genes) that can be employed to improve switchgrass seedling growth and establishment under soil drought conditions (Data are available via ProteomeXchange with identifier PXD004675). Full article

Protein-directed dynamic combinatorial chemistry is an emerging technique for efficient discovery of novel chemical structures for binding to a target protein. Typically, this method relies on a library of small molecules that react reversibly with each other to generate a combinatorial library. The components in the combinatorial library are at equilibrium with each other under thermodynamic control. When a protein is added to the equilibrium mixture, and if the protein interacts with any components of the combinatorial library, the position of the equilibrium will shift and those components that interact with the protein will be amplified, which can then be identified by a suitable biophysical technique. Such information is useful as a starting point to guide further organic synthesis of novel protein ligands and enzyme inhibitors. This review uses literature examples to discuss the practicalities of applying this method to inhibitor discovery, in particular, the set-up of the combinatorial library, the reversible reactions that may be employed, and the choice of detection methods to screen protein ligands from a mixture of reversibly forming molecules. Full article

We present the operational principle of a coherent Ising machine (CIM) based on a degenerate optical parametric oscillator (DOPO) network. A quantum theory of CIM is formulated, and the computational ability of CIM is evaluated by numerical simulation based on c-number stochastic differential equations. We also discuss the advanced CIM with quantum measurement-feedback control and various problems which can be solved by CIM. Full article

Mesoporous silica nanoparticles (MSNs) have been synthesized and loaded with both aluminum chloride phthalocyanine (AlClPc) and cisplatin as combinatorial therapeutics for treating cancer. The structural and photophysical properties of the MSN materials were characterized by different spectroscopic and microscopic techniques. Intracellular uptake and cytotoxicity were evaluated in human cervical cancer (HeLa) cells by confocal laser scanning microscopy (CLSM) and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays, respectively. The CLSM experiments showed that the MSN materials can be readily internalized in HeLa cells. The cytotoxic experiments demonstrated that, after light exposure, the combination of both AlClPc and cisplatin compounds in the same MSN platform potentiate the toxic effect against HeLa cells in comparison to the control AlClPc-MSN and cisplatin-MSN materials. These results show the potential of using MSN platforms as nanocarriers for combination photodynamic and chemotherapies to treat cancer. Full article

Post-transcriptional control of gene expression is mediated by RNA-binding proteins (RBPs) and small non-coding RNAs (e.g., microRNAs) that bind to distinct elements in their mRNA targets. Here, we review recent examples describing the synergistic and/or antagonistic effects mediated by RBPs and miRNAs to determine the localisation, stability and translation of mRNAs in mammalian cells. From these studies, it is becoming increasingly apparent that dynamic rearrangements of RNA-protein complexes could have profound implications in human cancer, in synaptic plasticity, and in cellular differentiation. Full article

Dynamic combinatorial chemistry has emerged as a promising tool for the discovery of complex receptors in supramolecular chemistry. At the heart of dynamic combinatorial chemistry are the reversible reactions that enable the exchange of building blocks between library members in dynamic combinatorial libraries (DCLs) ensuring thermodynamic control over the system. If more than one reversible reaction operates in a single dynamic combinatorial library, the complexity of the system increases dramatically, and so does its possible applications. One can imagine two reversible reactions that operate simultaneously or two reversible reactions that operate independently. Both these scenarios have advantages and disadvantages. In this contribution, we show how disulfide exchange and boronic ester transesterification can function simultaneous in dynamic combinatorial libraries under appropriate conditions. We describe the detailed studies necessary to establish suitable reaction conditions and highlight the analytical techniques appropriate to study this type of system. Full article

Regulated mRNA translation plays a key role in control of cell cycle progression in a variety of physiological and pathological processes, including in the self-renewal and survival of stem cells and cancer stem cells. While targeting mRNA translation presents an attractive strategy for control of aberrant cell cycle progression, mRNA translation is an underdeveloped therapeutic target. Regulated mRNAs are typically controlled through interaction with multiple RNA binding proteins (RBPs) but the mechanisms by which the functions of distinct RBPs bound to a common target mRNA are coordinated are poorly understood. The challenge now is to gain insight into these mechanisms of coordination and to identify the molecular mediators that integrate multiple, often conflicting, inputs. A first step includes the identification of altered mRNA ribonucleoprotein complex components that assemble on mRNAs bound by multiple, distinct RBPs compared to those recruited by individual RBPs. This review builds upon our knowledge of combinatorial control of mRNA translation during the maturation of oocytes from Xenopus laevis, to address molecular strategies that may mediate RBP diplomacy and conflict resolution for coordinated control of mRNA translational output. Continued study of regulated ribonucleoprotein complex dynamics promises valuable new insights into mRNA translational control and may suggest novel therapeutic strategies for the treatment of disease. Full article

Protein–protein interactions involving disordered partners have unique features and represent prominent targets in drug discovery processes. Intrinsically Disordered Proteins (IDPs) are involved in cellular regulation, signaling and control: they bind to multiple partners and these high-specificity/low-affinity interactions play crucial roles in many human diseases. Disordered regions, terminal tails and flexible linkers are particularly abundant in DNA-binding proteins and play crucial roles in the affinity and specificity of DNA recognizing processes. Protein complexes involving IDPs are short-lived and typically involve short amino acid stretches bearing few “hot spots”, thus the identification of molecules able to modulate them can produce important lead compounds: in this scenario peptides and/or peptidomimetics, deriving from structure-based, combinatorial or protein dissection approaches, can play a key role as hit compounds. Here, we propose a panoramic review of the structural features of IDPs and how they regulate molecular recognition mechanisms focusing attention on recently reported drug-design strategies in the field of IDPs. Full article

We describe a precision micropump for generation of precisely metered micro-aliquots of liquid at high rates. The use of custom designed piezoelectric valves positioned externally to the microfluidic chip allows for on-demand formation of micro-droplets with online control of their individual volumes from nLs to μLs at frequencies up to 400 Hz. The system offers precision of administering volumes of 1% and of time of emission of <0.5 ms. The use of a piezoelectric actuator provides two distinct vistas for controlling the volume of the droplets—either by digital control of the “open” interval or by analogue tuning of the lumen of the valve. Fast and precise generation of droplets make this system a perfect constituent module for microfluidic high-speed combinatorial screening schemes. Full article

In order to explore the synergistic mechanisms of combinatorial treatment using curcumin and mitomycin C (MMC) for breast cancer, MCF-7 breast cancer xenografts were conducted to observe the synergistic effect of combinatorial treatment using curcumin and MMC at various dosages. The synergistic mechanisms of combinatorial treatment using curcumin and MMC on the inhibition of tumor growth were explored by differential gene expression profile, gene ontology (GO), ingenuity pathway analysis (IPA) and Signal–Net network analysis. The expression levels of selected genes identified by cDNA microarray expression profiling were validated by quantitative RT-PCR (qRT-PCR) and Western blot analysis. Effect of combinatorial treatment on the inhibition of cell growth was observed by MTT assay. Apoptosis was detected by flow cytometric analysis and Hoechst 33258 staining. The combinatorial treatment of 100 mg/kg curcumin and 1.5 mg/kg MMC revealed synergistic inhibition on tumor growth. Among 1501 differentially expressed genes, the expression of 25 genes exhibited an obvious change and a significant difference in 27 signal pathways was observed (p < 0.05). In addition, Mapk1 (ERK) and Mapk14 (MAPK p38) had more cross-interactions with other genes and revealed an increase in expression by 8.14- and 11.84-fold, respectively during the combinatorial treatment by curcumin and MMC when compared with the control. Moreover, curcumin can synergistically improve tumoricidal effect of MMC in another human breast cancer MDA-MB-231 cells. Apoptosis was significantly induced by the combinatorial treatment (p < 0.05) and significantly inhibited by ERK inhibitor (PD98059) in MCF-7 cells (p < 0.05). The synergistic effect of combinatorial treatment by curcumin and MMC on the induction of apoptosis in breast cancer cells may be via the ERK pathway. Full article

During the last two decades, the manufacturing techniques of microfluidics-based devices have been phenomenally advanced, offering unlimited potential for bio-medical technologies. However, the direct applications of these technologies toward diagnostics and therapeutics are still far from maturity. The present challenges lay at the interfaces between the engineering systems and the biocomplex systems. A precisely designed engineering system with narrow dynamic range is hard to seamlessly integrate with the adaptive biological system in order to achieve the design goals. These differences remain as the roadblock between two fundamentally non-compatible systems. This paper will not extensively review the existing microfluidic sensors and actuators; rather, we will discuss the sources of the gaps for integration. We will also introduce system interface technologies for bridging the differences to lead toward paradigm shifts in diagnostics and therapeutics. Full article

The complex hide-and-seek game between HIV-1 and the host immune system has impaired the development of an efficient vaccine. In addition, the high variability of the virus impedes the long-term control of viral replication by small antiviral drugs. For more than 20 years, phage display technology has been intensively used in the field of HIV-1 to explore the epitope landscape recognized by monoclonal and polyclonal HIV-1-specific antibodies, thereby providing precious data about immunodominant and neutralizing epitopes. In parallel, biopanning experiments with various combinatorial or antibody fragment libraries were conducted on viral targets as well as host receptors to identify HIV-1 inhibitors. Besides these applications, phage display technology has been applied to characterize the enzymatic specificity of the HIV-1 protease. Phage particles also represent valuable alternative carriers displaying various HIV-1 antigens to the immune system and eliciting antiviral responses. This review presents and summarizes the different studies conducted with regard to the nature of phage libraries, target display mode and biopanning procedures. Full article

We analyze further the Magnus-Derek game, a two-player game played on a round table with n positions. The players jointly control the movement of a token. One player, Magnus, aims to maximize the number of positions visited while minimizing the number of rounds. The other player, Derek, attempts to minimize the number of visited positions. We present a new strategy for Magnus that succeeds in visiting the maximal number of positions in 3(n – 1) rounds, which is the optimal number of rounds up to a constant factor. Full article