Conceptual Proof Research Articles

Microneedle patch casting using a micromachined carbon master for enhanced drug delivery

For successful treatment of diseases, sufficient therapeutics must be provided to the body. Microneedle applications in therapeutic delivery and analytics sampling are restricted because of various issues, including smaller area for drug loading and analytics sampling. To achieve sufficient drug loading and analytics sampling and improve drug penetration while maintaining painless administration, patch-type microneedle arrays were designed and fabricated using polymer casting from a conical cavity mold. Microcavities were formed on a carbon plate via micromechanical machining. A porous polymer layer was coated on a microneedle patch (MNP). The pores of the porous polymer layer provided space and channels for drug delivery. A pH-sensitive polymer layer was employed to cap the porous polymer layer, which prevented drug leakage during storage and provided a stimulus drug release in response to body pH conditions. The drug can be delivered through holes connected to both sides of the patch. The drug release of the MNP was investigated in vitro and in vivo and showed conceptual proof that these MNs have the potential to enhance treatment protocols for various diseases with the flexibility of coating and therapeutic materials and offer significant scope for further variations and advancement.

Discovery and Characterization of VU0542270, the First Selective Inhibitor of Vascular Kir6.1/SUR2B KATP Channels.

Vascular smooth muscle KATP channels critically regulate blood flow and blood pressure by modulating vascular tone and therefore represent attractive drug targets for treating several cardiovascular disorders. However, the lack of potent inhibitors that can selectively inhibit Kir6.1/SUR2B (vascular KATP) over Kir6.2/SUR1 (pancreatic KATP) has eluded discovery despite decades of intensive research. We therefore screened 47,872 chemically diverse compounds for novel inhibitors of heterologously expressed Kir6.1/SUR2B channels. The most potent inhibitor identified in the screen was an N-aryl-N'-benzyl urea compound termed VU0542270. VU0542270 inhibits Kir6.1/SUR2B with an IC50 of approximately 100 nM but has no apparent activity toward Kir6.2/SUR1 or several other members of the Kir channel family at doses up to 30 µM (>300-fold selectivity). By expressing different combinations of Kir6.1 or Kir6.2 with SUR1, SUR2A, or SUR2B, the VU0542270 binding site was localized to SUR2. Initial structure-activity relationship exploration around VU0542270 revealed basic texture related to structural elements that are required for Kir6.1/SUR2B inhibition. Analysis of the pharmacokinetic properties of VU0542270 showed that it has a short in vivo half-life due to extensive metabolism. In pressure myography experiments on isolated mouse ductus arteriosus vessels, VU0542270 induced ductus arteriosus constriction in a dose-dependent manner similar to that of the nonspecific KATP channel inhibitor glibenclamide. The discovery of VU0542270 provides conceptual proof that SUR2-specific KATP channel inhibitors can be developed using a molecular target-based approach and offers hope for developing cardiovascular therapeutics targeting Kir6.1/SUR2B. SIGNIFICANCE STATEMENT: Small-molecule inhibitors of vascular smooth muscle KATP channels might represent novel therapeutics for patent ductus arteriosus, migraine headache, and sepsis; however, the lack of selective channel inhibitors has slowed progress in these therapeutic areas. Here, this study describes the discovery and characterization of the first vascular-specific KATP channel inhibitor, VU0542270.

Self-Assembled Supported Ionic Liquids.

Separation and reuse of the catalytically active metal complexes are persistent issues in homogeneous catalysis. Supported Ionic Liquid Phase (SILP) catalysts, where the catalytic center is dissolved in a thin film of a stable ionic liquid, deposited on a solid support, present a promising alternative. However, the dissolution of the metal center in the film leaves little control over its position and its activity. We present here four novel, task-specific ionic liquids [FPhn ImH R]I (n=1, 2; R=PEG2 , C12 H25 ), designed to self-assemble on a silica surface without any covalent bonding and offering a metal binding site in a controlled distance to the support. Advanced multinuclear solid-state NMR spectroscopic techniques under Magic Angle Spinning, complemented by molecular dynamics (MD) simulations, allow us to determine their molecular conformation when deposited inside SBA-15 as a model silica support. We provide here conceptual proof for a rational design of ionic liquids self-assembling into thin films, opening an avenue for a second, improved generation of SILP catalysts.

Development of chimeric protein as a multivalent vaccine for human Kinetoplastid infections: Chagas disease and leishmaniasis

Leishmania spp. and Trypanosoma cruzi are parasitic kinetoplastids of great medical and epidemiological importance since they are responsible for thousands of deaths and disability-adjusted life-years annually, especially in low- and middle-income countries. Despite efforts to minimize their impact, current prevention measures have failed to fully control their spread. There are still no vaccines available. Taking into account the genetic similarity within the Class Kinetoplastida, we selected CD8+ T cell epitopes preserved among Leishmania spp. and T. cruzi to construct a multivalent and broad-spectrum chimeric polyprotein vaccine. In addition to inducing specific IgG production, immunization with the vaccine was able to significantly reduce parasite burden in the colon, liver and skin lesions from T. cruzi, L. infantum and L. mexicana challenged mice, respectively. These findings were supported by histopathological analysis, which revealed decreased inflammation in the colon, a reduced number of degenerated hepatocytes and an increased proliferation of connective tissue in the skin lesions of the corresponding T. cruzi, L. infantum and L. mexicana vaccinated and challenged mice. Collectively, our results support the protective effect of a polyprotein vaccine approach and further studies will elucidate the immune profile associated with this protection. Noteworthy, our results act as conceptual proof that a single multi-kinetoplastida vaccine can be used effectively to control different infectious etiologies, which in turn can have a profound impact on the development of a new generation of vaccines.

The Sphere of Semiadditive Height 1

Abstract We construct a lift of the $p$-complete sphere to the universal height $1$ higher semiadditive stable $\infty $-category of Carmeli–Schlank–Yanovski, providing a counterexample, at height $1$, to their conjecture that the natural functor $ _n \to \operatorname{\textrm{Sp}}_{T(n)}$ is an equivalence. We then record some consequences of the construction, including an observation of Schlank that this gives a conceptual proof of a classical theorem of Lee on the stable cohomotopy of Eilenberg–MacLane spaces.

Sextactic points on the Fermat cubic curve and arrangements of conics

The purpose of this note is to report, in narrative rather than rigorous style, about the nice geometry of 6-division points on the Fermat cubic F and various conics naturally attached to them. Most facts presented here were derived by symbolic algebra programs and the idea of the note is to propose a research direction in the search of conceptual proofs of facts stated here and their generalisations. Extensions in several directions seem possible (taking curves of higher degree and contact to F, studying higher degree curves passing through higher order division points on F, studying curves passing through intersection points of already constructed curves, taking the duals etc.) and we hope some younger colleagues might find pleasure in following proposed paths as well as finding their own.

Finite free cumulants: Multiplicative convolutions, genus expansion and infinitesimal distributions

Given two polynomials p ( x ) , q ( x ) p(x), q(x) of degree d d , we give a combinatorial formula for the finite free cumulants of p ( x ) ⊠ d q ( x ) p(x)\boxtimes _d q(x) . We show that this formula admits a topological expansion in terms of non-crossing multi-annular permutations on surfaces of different genera. This topological expansion, on the one hand, deepens the connection between the theories of finite free probability and free probability, and in particular proves that ⊠ d \boxtimes _d converges to ⊠ \boxtimes as d d goes to infinity. On the other hand, borrowing tools from the theory of second order freeness, we use our expansion to study the infinitesimal distribution of certain families of polynomials which include Hermite and Laguerre, and draw some connections with the theory of infinitesimal distributions for real random matrices. Finally, building on our results we give a new short and conceptual proof of a recent result (see J. Hoskins and Z. Kabluchko [Exp. Math. (2021), pp. 1–27]; S. Steinerberger [Exp. Math. (2021), pp. 1–6]) that connects root distributions of polynomial derivatives with free fractional convolution powers.

Davydov-Yetter cohomology, comonads and Ocneanu rigidity

Davydov-Yetter cohomology classifies infinitesimal deformations of tensor categories and of tensor functors. Our first result is that Davydov-Yetter cohomology for finite tensor categories is equivalent to the cohomology of a comonad arising from the central Hopf monad. This has several applications: First, we obtain a short and conceptual proof of Ocneanu rigidity. Second, it allows to use standard methods from comonad cohomology theory to compute Davydov-Yetter cohomology for a family of non-semisimple finite-dimensional Hopf algebras generalizing Sweedler's four dimensional Hopf algebra.

Asymptotic Gaussianity via coalescence probabilities in the Hammond-Sheffield urn

For the renormalised sums of the random $\pm 1$-colouring of the connected components of $\mathbb Z$ generated by the coalescing renewal processes in the "power law P\'olya's urn" of Hammond and Sheffield we prove functional convergence towards fractional Brownian motion, closing a gap in the tightness argument of their paper. In addition, in the regime of the strong renewal theorem we gain insights into the coalescing renewal processes in the Hammond-Sheffield urn (such as the asymptotic depth of most recent common ancestors) and are able to control the coalescence probabilities of two, three and four individuals that are randomly sampled from $[n]$. This allows us to obtain a new, conceptual proof of the asymptotic Gaussianity (including the functional convergence) of the renormalised sums of more general colourings, which can be seen as an invariance principle beyond the main result of Hammond and Sheffield. In this proof, a key ingredient of independent interest is a sufficient criterion for the asymptotic Gaussianity of the renormalised sums in randomly coloured random partitions of $[n]$, based on Stein's method. Along the way we also prove a statement on the asymptotics of the coalescence probabilities in the long-range seedbank model of Blath, Gonz\'alez Casanova, Kurt, and Span\`o.

The Rectangle Complex of a Relation

We construct a simplicial complex, the rectangle complex of a relation R, and show that it is homotopy equivalent to the Dowker complex of R. This results in a short and conceptual proof of functorial versions of Dowker’s Theorem used in topological data analysis.

Classification of strongly asymptotically log del Pezzo flags and surfaces

We introduce the notion of strongly asymptotically log del Pezzo flags, and classify such flags under the assumption that their zero-dimensional part lies in the boundary. We use this result to give a new and conceptual proof of the classification of strongly asymptotically log del Pezzo surfaces, originally due to Cheltsov and Rubinstein.

Covalent and Oriented Immobilization of Antibodies through Systematic Modification of Photoactivatable RNA Hybrid Aptamers

We report a covalent and well-oriented strategy of immobilization of antibodies using photoactivatable Fc-binding RNA aptamers (FcBAs). We prepared several types of FcBAs that were further modified with photoaffinity probes (i.e., benzophenone or diazirine), and evaluated the binding capabilities and the photo-crosslinking efficiency of them via pull-down assays and fluorescence analyses, respectively. Initial moderate photo-crosslinking efficiency (Kd ∼ 110 nM) was substantially improved by multivalent association of FcBAs and structural modification of FcBAs. For a conceptual proof, covalent crosslinking of human IgG on FcBA-tethered solid chips was fabricated and investigated by scanometry, which eventually proved real applicability of the present scheme toward immunoassays.

On multiplication formulas of affine q-Schur algebras

We provide a simple and conceptual proof of Du-Fu's multiplication formula of affine q -Schur algebras via Lusztig's formula. We use the multiplication formulas to provide a proof of the existence of generic affine Schur algebras, in return, and a formula of the generators under comultiplication.

Analytic properties of heat equation solutions and reachable sets

There recently has been some interest in the space of functions on an interval satisfying the heat equation for positive time in the interior of this interval. Such functions were characterised as being analytic on a square with the original interval as its diagonal. In this short note we provide a direct argument that the analogue of this result holds in any dimension. For the heat equation on a bounded Lipschitz domain (Omega subset mathbb {R}^{d}) at positive time all solutions are analytically extendable to a geometrically determined subdomain {mathcal {E}}(Omega ) of {mathbb {C}}^d containing (Omega ). This domain is sharp in the sense that there is no larger domain for which this is true. If (Omega ) is a ball we prove an almost converse of this theorem. Any function that is analytic in an open neighbourhood of {mathcal {E}}(Omega ) is reachable in the sense that it can be obtained from a solution of the heat equation at positive time. This is based on an analysis of the convergence of heat equation solutions in the complex domain using the boundary layer potential method for the heat equation. The converse theorem is obtained using a Wick rotation into the complex domain that is justified by our results. This gives a simple explanation for the shapes appearing in the one-dimensional analysis of the problem in the literature. It also provides a new short and conceptual proof in that case.

Coxeter group actions on interacting particle systems

We provide a conceptual proof of the color–position symmetry of colored ASEP by relating it to the actions of Coxeter groups. The group action (and hence the color–position symmetry) also applies to more general interacting particle systems, such as the colored ASEP(q,j) or systems with open boundary conditions. As an application, we find the asymptotics of the expected positions of second-class particles in the ASEP(q,j).

Multifunctional hybrid films from sudan III and multiwalled carbon nanotubes: electrical conduction and photoinduced molecular orientation

Multifunctional materials (MFMs) can be an important system because of their capacity to combine different properties useful for electronic devices. Multiwalled carbon nanotubes (MWCNTs) and azobenzene derivate Sudan III (SIII) are compounds with great potential to form this type of system. These compounds exhibit properties of electrical conduction and photoinduced molecular orientation, respectively, which can be combined in a single film-shaped system. In this study, we report on the fabrication and characterization of multifunctional hybrid films created from SIII mixed with MWCNTs via both Langmuir and Langmuir–Blodgett (LB) techniques. For SIII+MWCNTs monolayers obtained using the Langmuir technique, the surface pressure isotherms revealed that the aggregation process of pure SIII drives the formation of monolayers. Brewster angle microscopy of the monolayers indicated that MWCNTs form loop-shaped structures resembling rings. Such structures were not present in films of pure MWCNTs or pure SIII. The current–voltage characteristic curve showed that the films have an ohmic behavior associated to free electrons in MWCNTs, exhibiting conductivity on the order of that of semiconductors. The SIII+MWCNTs LB films exhibited a photoinduced molecular orientation determined via SIII photoisomerization. These processes, occurring in a single film, are the conceptual proof that these systems are MFMs with potential applications in developing hybrid devices.

Lax matrices from antidominantly shifted Yangians and quantum affine algebras: A-type

We construct a family of GLn rational and trigonometric Lax matrices TD(z) parametrized by Λ+-valued divisors D on P1. To this end, we study the shifted Drinfeld Yangians Yμ(gln) and quantum affine algebras Uμ+,μ−(Lgln), which slightly generalize their sln-counterparts of [3,18]. Our key observation is that both algebras admit the RTT type realization when μ (resp. μ+ and μ−) are antidominant coweights. We prove that TD(z) are polynomial in z (up to a rational factor) and obtain explicit simple formulas for those linear in z. This generalizes the recent construction by the first two authors of linear rational Lax matrices [15] in both trigonometric and higher z-degree directions. Furthermore, we show that all TD(z) are normalized limits of those parametrized by D supported away from {∞} (in the rational case) or {0,∞} (in the trigonometric case). The RTT approach provides conceptual and elementary proofs for the construction of the coproduct homomorphisms on shifted Yangians and quantum affine algebras of sln, previously established in [14,18] via rather tedious computations. Finally, we establish a close relation between a certain collection of explicit linear Lax matrices and the well-known parabolic Gelfand-Tsetlin formulas.

General-Purpose Architectural Model for IoT-Based In-situ Monitoring Systems

Over time, the Internet of things (IoT) discussion has come to prominence, and in-situ monitoring systems have been geared up with IoT services and deployed over IoT architectures. The integration of IoT services within system development has enriched many monitoring application studies but the architectural models used in majority of these studies trivializes several key components of a fully functional IoT architecture. This paper proposes a general-purpose architectural model (GPAM) that can be used in the deployment of any in-situ monitoring system. The proposed architectural model is successfully implemented using a single domain use-case (water assessment) as a conceptual proof. The traditional water assessment processes are transformed into IoT processes in an attempt to reach the same result in a more efficient manner. This template can help prospective developers build and engineer robust IoT monitoring systems.

Design and Installation of an Agent-Controlled Cyber-Physical Production System Using the Example of a Beverage Bottling Plant

The design of production plants in the form of a cyber-physical production system (CPPS) promises rapid adaptability to changing market requirements, high flexibility during production, and robust behavior in the event of failure and offers the possibility of integrating customers into the production process. In contradiction to these advantages, there are both a low penetration and a still low technology readiness level of operational CPPS. This article, therefore, presents a production system for customized beverage bottling, consisting of industrial resources from well-known machine builders and designed as a CPPS through the use of a multiagent system. The premise that all products are to be manufactured in a saleable form should clarify the claim of the CPPS to be classified as an industrial plant. Its functionality is tested through an evaluation based on two use cases with different requirements. This conceptual proof should enable the future practice-oriented investigation of urgent questions from research and industry. As a further result, a complete test method for the development and commissioning of a CPPS, starting with the design phase and ending with a valid reliable production system, is shown.

КОНЦЕПТУАЛЬНИЙ ПІДХІД МЕТОДОЛОГІЇ ПІДГОТОВКИ ЗВІТНИХ ДАНИХ У ПОРІВНЯЛЬНИЙ ВИГЛЯД ПРИ РОЗРАХУНКУ ПОКАЗНИКІВ ФІНАНСОВОГО СТАНУ

Calculation of financial standing indicators based on financial reporting forms (complete or simplified) contains a set of measures, which should be observed in a strict sequence (bringing data into comparative form; determining criteria and in-dicators for assessing financial standing; calculating indicators for the period under review; assessing financial condition by indicators over time; developing specific measures and making managerial decisions) to perform high-end economic analysis, the purpose of which is also preventing information distortion in the justification of effective management decisions at the micro and macro levels. Prevention of erroneous conclusions becomes possible already at the first stage of implementing economic research – bringing the data into a comparative form. Currently, in addition to the definitions of the main terms regarding the composition of financial statements which are included in the legislation, there are practically no scientific studies on the correctness of applying financial standing indicators in calculations using financial reporting indicators of various types – at the reporting date and for the reporting period, despite they are in one corresponding reporting period (quarter, half-year, year). The publication presents conceptual methodological approaches to ensuring comparability of financial reporting indicators for calculating and analyzing financial standing indicators provided comprehensive information content is accessible of reporting data over time. In view of the lack of methodology in this area, conceptual methodological approaches have been developed to assess the comparability of financial reporting indicators and, if necessary, to bring its indicators to a comparable form for calculating financial standing indicators. The developed conceptual approaches are the basis for further alternative model-ing, depending on the purpose of the study and other factors, such as the comprehensive information content of reporting data over time. As a result of the scientific development, the author of the study has provided conceptual proof of the expediency of conducting annual reports and interim reports in the analysis, the methodological need to bring its indicators to a comparable form for calculating financial standing indicators using special procedures, such as calculating the "arithmetic mean balance sheet" and preparing a "settlement statement of financial standing", respectively, depending on the time parameter of reporting. The relevance of the procedure for preparing reporting data for a comparable form before the fundamental analysis is proved.