Combinatorial Design Research Articles

High-throughput screening of nanoparticles in drug delivery.

The use of pharmacologically active compounds to manage and treat diseases is of utmost relevance in clinical practice. It is well recognized that spatial-temporal control over the delivery of these biomolecules will greatly impact their pharmacokinetic profile and ultimately their therapeutic effect. Nanoparticles (NPs) prepared from different materials have been tested successfully in the clinic for the delivery of several biomolecules including non-coding RNAs (siRNA and miRNA) and mRNAs. Indeed, the recent success of mRNA vaccines is in part due to progress in the delivery systems (NP based) that have been developed for many years. In most cases, the identification of the best formulation was done by testing a small number of novel formulations or by modification of pre-existing ones. Unfortunately, this is a low throughput and time-consuming process that hinders the identification of formulations with the highest potential. Alternatively, high-throughput combinatorial design of NP libraries may allow the rapid identification of formulations with the required release and cell/tissue targeting profile for a given application. Combinatorial approaches offer several advantages over conventional methods since they allow the incorporation of multiple components with varied chemical properties into materials, such as polymers or lipid-like materials, that will subsequently form NPs by self-assembly or chemical conjugation processes. The current review highlights the impact of high-throughput in the development of more efficient drug delivery systems with enhanced targeting and release kinetics. It also describes the current challenges in this research area as well as future directions.

On the subset sum problem for finite fields

Let G be the additive group of a finite field. J. Li and D. Wan determined the exact number of solutions of the subset sum problem over G, by giving an explicit formula for the number of subsets of G of prescribed size whose elements sum up to a given element of G. They also determined a closed-form expression for the case where the subsets are required to contain only nonzero elements. In this paper we give an alternative proof of the two formulas. Our argument is purely combinatorial, as in the original proof by Li and Wan, but follows a different and somehow more “natural” approach. We also indicate some new connections with coding theory and combinatorial designs.

Control of APOBEC3B induction and cccDNA decay by NF-κB and miR-138-5p

Background & AimsImmune-mediated induction of cytidine deaminase APOBEC3B (A3B) expression leads to HBV covalently closed circular DNA (cccDNA) decay. Here, we aimed to decipher the signalling pathway(s) and regulatory mechanism(s) involved in A3B induction and related HBV control.MethodsDifferentiated HepaRG cells (dHepaRG) knocked-down for NF-κB signalling components, transfected with siRNA or micro RNAs (miRNA), and primary human hepatocytes ± HBV or HBVΔX or HBV-RFP, were treated with lymphotoxin beta receptor (LTβR)-agonist (BS1). The biological outcomes were analysed by reverse transcriptase-qPCR, immunoblotting, luciferase activity, chromatin immune precipitation, electrophoretic mobility-shift assay, targeted-bisulfite-, miRNA-, RNA-, genome-sequencing, and mass-spectrometry.ResultsWe found that canonical and non-canonical NF-κB signalling pathways are mandatory for A3B induction and anti-HBV effects. The degree of immune-mediated A3B production is independent of A3B promoter demethylation but is controlled post-transcriptionally by the miRNA 138-5p expression (hsa-miR-138-5p), promoting A3B mRNA decay. Hsa-miR-138-5p over-expression reduced A3B levels and its antiviral effects. Of note, established infection inhibited BS1-induced A3B expression through epigenetic modulation of A3B promoter. Twelve days of treatment with a LTβR-specific agonist BS1 is sufficient to reduce the cccDNA pool by 80% without inducing significant damages to a subset of cancer-related host genes. Interestingly, the A3B-mediated effect on HBV is independent of the transcriptional activity of cccDNA as well as on rcDNA synthesis.ConclusionsAltogether, A3B represents the only described enzyme to target both transcriptionally active and inactive cccDNA. Thus, inhibiting hsa-miR-138-5p expression should be considered in the combinatorial design of new therapies against HBV, especially in the context of immune-mediated A3B induction.Lay summaryImmune-mediated induction of cytidine deaminase APOBEC3B is transcriptionally regulated by NF-κB signalling and post-transcriptionally downregulated by hsa-miR-138-5p expression, leading to cccDNA decay. Timely controlled APOBEC3B-mediated cccDNA decay occurs independently of cccDNA transcriptional activity and without damage to a subset of cancer-related genes. Thus, APOBEC3B-mediated cccDNA decay could offer an efficient therapeutic alternative to target hepatitis B virus chronic infection.

Hamming weight enumerators of multi-twisted codes with at most two non-zero constituents

In this paper, we explicitly determine Hamming weight enumerators of several classes of multi-twisted codes over finite fields with at most two non-zero constituents, where each non-zero constituent has dimension 1. Among these classes of multi-twisted codes, we further identify two classes of optimal equidistant linear codes that have nice connections with the theory of combinatorial designs and several other classes of minimal linear codes that are useful in constructing secret sharing schemes with nice access structures. We also illustrate our results with some examples.

Alternative method for canagliflozin oxidation analysis using an electrochemical flow cell – Comparative study

This paper highlights the potential of electrochemical flow cells for oxidative-stress testing of active pharmaceutical ingredients using canagliflozin as a model substance. Based on design of experiments, we developed our method through a reduced combinatorial design, optimizing the following independent variables: cell size, electrolyte flow rate, electrolyte concentration, and electrolyte pH. Using ammonium phosphate buffer with methanol in a 50/50 vol ratio as a working electrolyte, we electrochemically oxidized samples and analyzed them by high-performance liquid chromatography, considering the following dependent variables: peak area of each impurity, peak area of canagliflozin, and the percentage of the corresponding peak areas. Our results showed that the most significant independent variables were electrolyte pH and flow rate. By data optimization, we determined the most suitable conditions for electrochemical oxidation of canagliflozin, namely 50 µm cell size, 300 mM electrolyte concentration, 0.1 mL/h electrolyte flow rate, and electrolyte pH = 4. The repeatability of the method, expressed as the relative standard deviation of the canagliflozin peak area, measured in ten separately oxidized samples, was 1.64%. For comparison purposes, we performed a degradation experiment using hydrogen peroxide, identifying five identical impurities in both cases, as confirmed by mass spectrometry. The degradation products formed when using the chemical method after 1, 3, and 7 days totaled 0.09%, 0.75%, and 3.75%, respectively, and the degradation products formed when using the electrochemical method after 3 h totaled 3.11%. Oxidation with hydrogen peroxide required 7 days, whereas electrochemical oxidation was completed in 3 h. Overall, the electrochemical method significantly saves time and reduces the consumption of active ingredients and solvents thanks to the miniaturized size of the electrochemical cell, thereby minimizing the costs of forced degradation studies.

Anaerobic digestion of corn straw pretreated by ultrasonic combined with aerobic hydrolysis

Corn straw (CS) was pretreated by ultrasonic combined aerobic with biogas slurry as medium for anaerobic digestion (AD), that strengthened the degradation efficiency CS, varied in the composition of digestion slurry, thereby the methane production was increased. Central combinatorial design (CCD) test was used to treat CS at ultrasonic power (200, 400, and 600 W), time (10, 20, and 30 min) and AD for 25 days, at 37 ± 1℃. According to data showed that the pH and volatile fatty acids (VFAs) affected methane production directly. With an ultrasonic power 309 W, time 26 min, it reached the maximum content of VFAs with 16.24 g/L, the cumulative methane production achieved the highest with 198.56 mL/g VS, which was 46.73% higher than unpretreated raw material as CK. Ultrasonic-aerobic hydrolysis pretreatment can obtain higher VFAs and methane production content in a short period of time that is great significance to biogas engineering.

A complete characterization of bidegreed split graphs with four distinct signless Laplacian eigenvalues

It is a well-known fact that a graph of diameter d has at least d+1 eigenvalues (A.E. Brouwer, W.H. Haemers (2012) [2]). A graph is d-extremal (resp. dSL-extremal) if it has diameter d and exactly d+1 distinct eigenvalues (resp. signless Laplacian eigenvalues), and a graph is split if its vertex set can be partitioned into a clique and a stable set. Such graphs have diameter at most three. If all vertex degrees in a split graph are either d˜ or dˆ, then we say it is (d˜,dˆ)-bidegreed. In this paper, we present a complete classification of the connected bidegreed 3SL-extremal split graphs using the association of split graphs with combinatorial designs.

Finding Compositional Inverses of Permutations From the AGW Criterion

Permutation polynomials and their compositional inverses have wide applications in cryptography, coding theory, and combinatorial designs. Motivated by several previous results on finding compositional inverses of permutation polynomials of different forms, we propose a general method for finding these inverses of permutation polynomials constructed by the AGW criterion. As a result, we have reduced the problem of finding the compositional inverse of such a permutation polynomial over a finite field to that of finding the inverse of a bijection over a smaller set. We demonstrate our method by interpreting several recent known results, as well as by providing new explicit results on more classes of permutation polynomials in different types. In addition, we give new criteria for these permutation polynomials being involutions. Explicit constructions are also provided for all involutory criteria.

An enhanced stochastic operating cycle description including weather and traffic models

• The new stochastic operating cycle includes models for the weather and traffic. • A primary model for the weather category is introduced to account for seasonality. • A regression analysis is made to investigate spread in CO 2 emissions. • It is found that both seasonal and traffic settings influence CO 2 emissions. The present paper extends the concept of a stochastic operating cycle (sOC) by introducing additional models for weather and traffic. In regard to the weather parameters, dynamic models for air temperature, atmospheric pressure, relative humidity, precipitation, wind speed and direction are included. The traffic models is instead based on a macroscopic approach which describes the density dynamically by means of a simple autoregressive process. The enhanced format is structured in a hierarchical fashion, allowing for ease of implementation and modularity. The novel models are parametrised starting from data available from external databases. The possibility of generating synthetic data using the statistical descriptors introduced in the paper is also discussed. To investigate the impact of the novel parameters over energy efficiency, a sensitivity analysis is conducted with a combinatorial test design. Simulation results show that both seasonality and traffic conditions are responsible for introducing major variations in the CO 2 emissions.

QUANTUM COMBINATORIAL DESIGN

AbstractCombinatorial Design such as configuration design, design optioneering, component selection, and generative design, is common across engineering. Generating solutions for a combinatorial design task often involves the application of classical computing solvers that can either map or navigate design spaces. However, it has been observed that classical computing resource power-law scales with many design space models. This observation suggests classical computing may not be capable of modelling our future design space needs.To meet future design space modelling needs, this paper examines quantum computing and the characteristics that enables its resources to scale polynomially with design space size. The paper then continues to present a combinatorial design problem that is subsequently represented, constrained and solved by quantum computing. The results of which are the derivation of an initial set of circuits that represent design space constraints. The study shows the game-changing possibilities of quantum computing as an engineering design tool and is the start of an exciting new journey for design research.

On the Synthesis of Systems Possessing the Structure of Some Combinatorial Designs

On the Synthesis of Systems Possessing the Structure of Some Combinatorial Designs

A Scalable Key Pre-distribution Scheme based on the Unital Design for the Internet of Things Security

In recent years, the Internet of Things (IoT) has swept through most aspects of people lives, where all objects are connected to a common network. Therefore, the security of IoT devices is naturally crucial. As for the constrained resources of IoT devices, we need to have lightweight encryption algorithms. Accordingly, the symmetric key establishment is a favourite paradigm for securing IoT. In this study, a key pre-distribution scheme (KPS) has been proposed based on the combinatorial design for IoT. The proposed KPS has been created to increase network scalability. Therefore, a combinatorial design called the unital design has been applied for the establishment of keys. In the present scheme, a kind of mapping has been proposed from the unital design to the key establishment, which yields a network with high scalability. The results indicate that the present scheme increases network scalability considerably with high resilience.

Prototyping of microbial chassis for the biomanufacturing of high-value chemical targets

Metabolic engineering technologies have been employed with increasing success over the last three decades for the engineering and optimization of industrial host strains to competitively produce high-value chemical targets. To this end, continued reductions in the time taken from concept, to development, to scale-up are essential. Design-Build-Test-Learn pipelines that are able to rapidly deliver diverse chemical targets through iterative optimization of microbial production strains have been established. Biofoundries are employing in silico tools for the design of genetic parts, alongside combinatorial design of experiments approaches to optimize selection from within the potential design space of biological circuits based on multi-criteria objectives. These genetic constructs can then be built and tested through automated laboratory workflows, with performance data analysed in the learn phase to inform further design. Successful examples of rapid prototyping processes for microbially produced compounds reveal the potential role of biofoundries in leading the sustainable production of next-generation bio-based chemicals.

Combinatorial library design and virtual screening of cryptolepine derivatives against topoisomerase IIA by molecular docking and DFT studies

Abstract Various computational approaches have received ever-growing role in the design of potential inhibitors of the topoisomerase 2 (TOP2A) for cancer treatment. TOP2A plays a key role in the deoxyribonucleic acid (DNA) replication before cell division and thus facilitates the growth of cells. This TOP2A function can be suppressed by targeting it with potential inhibitors in cancer cells to terminate the uncontrolled cell division. Among potential inhibitors, cryptolepine has higher selectivity along with the ability to intercalate into DNA, effectively blocking TOP2A and ceasing cell division in cancer cells. However, this compound has drawbacks of being nonspecific and possessing relatively low affinity. Therefore, a combinatorial library of 31,114 cryptolepine derivatives was designed and virtually screened by molecular docking to predict the molecular interactions between the cryptolepine derivatives and TOP2A using cryptolepine as a standard. All the binding poses of cryptolepine derivatives for TOP2A were investigated to calculate binding energy. The compounds with the database numbers 8618, 907, 147, 16755, and 8186 scored the highest binding energies, −9.88, −9.76, −9.75, −9.73, and −9.72 kcal/mol, respectively, and the highest binding affinities while the cryptolepine binding energy is −6.09 kcal/mol. The strong binding interactions of these derivatives show that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of these derivatives with different amino acid residues were also observed and analyzed. A comprehensive understanding of the interactions of the proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This computational study suggests useful references to understand inhibition mechanisms that will help in the further modifications of TOP2A inhibitors. Moreover, the DFT study of the derivatives with the highest binding energies was performed, helping to further understand the binding affinities of these compounds.

Designs in Finite Metric Spaces: A Probabilistic Approach

A finite metric space is called here distance degree regular if its distance degree sequence is the same for every vertex. A notion of designs in such spaces is introduced that generalizes that of designs in Q-polynomial distance-regular graphs. An approximation of their cumulative distribution function, based on the notion of Christoffel function in approximation theory is given. As an application we derive limit laws on the weight distributions of binary orthogonal arrays of strength going to infinity. An analogous result for combinatorial designs of strength going to infinity is given.

Large sets with multiplicity

Large sets of combinatorial designs has always been a fascinating topic in design theory. These designs form a partition of the whole space into combinatorial designs with the same parameters. In particular, a large set of block designs, whose blocks are of size k taken from an n-set, is a partition of all the k-subsets of the n-set into disjoint copies of block designs, defined on the n-set, and with the same parameters. The current most intriguing question in this direction is whether large sets of Steiner quadruple systems exist and to provide explicit constructions for those parameters for which they exist. In view of its difficulty no one ever presented an explicit construction even for one nontrivial order. Hence, we seek for related generalizations. As generalizations, to the existence question of large sets, we consider two related questions. The first one is to provide constructions for sets on Steiner systems in which each block (quadruple or a k-subset) is contained in exactly $$\mu $$ systems. The constructions of such systems also yield secure protocols for the generalized Russian cards problem. The second question is to provide constructions for large set of H-designs (mainly for quadruples, but also for larger block size), which have applications in threshold schemes and in quantum jump codes. We prove the existence of such systems for many parameters using orthogonal arrays, perpendicular arrays, ordered designs, sets of permutations, and one-factorizations of the complete graph.

Oligomodal metamaterials with multifunctional mechanics

Mechanical metamaterials are artificial composites that exhibit a wide range of advanced functionalities such as negative Poisson's ratio, shape shifting, topological protection, multistability, extreme strength-to-density ratio, and enhanced energy dissipation. In particular, flexible metamaterials often harness zero-energy deformation modes. To date, such flexible metamaterials have a single property, for example, a single shape change, or are pluripotent, that is, they can have many different responses, but typically require complex actuation protocols. Here, we introduce a class of oligomodal metamaterials that encode a few distinct properties that can be selectively controlled under uniaxial compression. To demonstrate this concept, we introduce a combinatorial design space containing various families of metamaterials. These families include monomodal (i.e., with a single zero-energy deformation mode); oligomodal (i.e., with a constant number of zero-energy deformation modes); and plurimodal (i.e., with many zero-energy deformation modes), whose number increases with system size. We then confirm the multifunctional nature of oligomodal metamaterials using both boundary textures and viscoelasticity. In particular, we realize a metamaterial that has a negative (positive) Poisson's ratio for low (high) compression rate over a finite range of strains. The ability of our oligomodal metamaterials to host multiple mechanical responses within a single structure paves the way toward multifunctional materials and devices.

Generalization of MacNeish’s Kronecker product theorem of mutually orthogonal Latin squares

The subject of mutually orthogonal Latin squares (MOLSs) has fascinated researchers for many years. Although there is a number of intriguing results in this area, many open problems remain to which the answers seem as elusive as ever. Mutually orthogonal graph squares (MOGSs) are considered a generalization to MOLS. MOLS are considered an area of combinatorial design theory which has many applications in optical communications, cryptography, storage system design, wireless communications, communication protocols, and algorithm design and analysis, to mention just a few areas. In this paper, we introduce a technique for constructing the mutually orthogonal disjoint union of graphs squares and the generalization of the Kronecker product of MOGS as a generalization to the MacNeish’s Kronecker product of MOLS. These are useful for constructing many new results concerned with the MOGS.

A survey of key pre-distribution schemes based on combinatorial designs for resource-constrained devices in the IoT network

Currently, IoT is being used as a novel tool in many applications. Some applications use the end nodes such as wireless sensor network, RFID and embedded systems referred to as resource-constrained devices. These devices have limitations in computing and communication power, memory capacity and power. One of the approaches to discuss key distribution in these devices is to apply and use key pre-distribution schemes (KPSs) as a lightweight solution. Also, the combinatorial designs application in key pre-distribution has been considered as a suitable method due to the low overhead in the shared key discovery phase between devices. This paper assessed the combinatorial designs used in key pre-distribution, and then, compared these designs using KPSs evaluation metrics. Finally, by tabulating all the considered key pre-distribution methods in a comparison table, it was stated that all of these methods could be used in different applications depending on their strengths.

Combinatorial Design of a Sialic Acid-Imprinted Binding Site.

Aberrant glycosylation has been proven to correlate with various diseases including cancer. An important alteration in cancer progression is an increased level of sialylation, making sialic acid one of the key constituents in tumor-specific glycans and an interesting biomarker for a diversity of cancer types. Developing molecularly imprinted polymers (MIPs) with high affinity toward sialic acids is an important task that can help in early cancer diagnosis. In this work, the glycospecific MIPs are produced using cooperative covalent/noncovalent imprinting. We report here on the fundamental investigation of this termolecular imprinting approach. This comprises studies of the relative contribution of orthogonally interacting functional monomers and their synergetic behavior and the choice of different counterions on the molecular recognition properties for the sialylated targets. Combining three functional monomers targeting different functionalities on the template led to enhanced imprinting factors (IFs) and selectivities. This apparent cooperative effect was supported by 1H NMR and fluorescence titrations of monomers with templates or template analogs. Moreover, highlighting the role of the template counterion use of tetrabutylammonium (TBA) salt of sialic acid resulted in better imprinting than that of sodium salts supported by both in solution interaction studies and in MIP rebinding experiments. The glycospecific MIPs display high affinity for sialylated targets, with an overall low binding of other nontarget saccharides.