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Zwitterionic polymers, ampholytic macromolecules containing ionic moieties of opposite sign on the same pendant groups, exhibit strong protein-repulsive properties and an inherent biological inertness. For that reason, these highly hydrated inner salt macromolecules have emerged as some of the most viable alternatives to poly(ethylene glycol) (PEG), a gold standard in enabling stealth behavior in life science applications. However, the structural diversity of polymer zwitterions remains limited, and currently available macromolecules do not possess an intrinsic ability to undergo hydrolytical degradation, an important prerequisite for use in drug delivery applications. The present paper reports on the synthesis of a zwitterionic polymer, a multimerized form (two thousand copies), of a biologically benign buffering agent, HEPES, which is covalently assembled on a polyphosphazene backbone. The polymer exhibits typical polyzwitterionic solution behavior, an environmentally dependent hydrolytic degradation pattern, and excellent in vitrocompatibility, features that highlight its potential utility for life science applications.

Microresonator optical frequency combs (OFCs) are of great interest for basic science and high-tech applications. Major attention is usually paid to the OFCs formed near pump frequency. Raman OFCs can also be generated in resonators at Stokes frequencies, but they are much less studied. This work reports a Raman OFC with spectral line spacing equal to a multiple of a free spectral range (FSR) that has not been observed in optical macro- and microresonators before. We experimentally attained a Raman spectrum with tripled FSR line spacing in a silica microsphere. Numerical modeling of the Lugiato-Lefever equation shows that this experimental OFC may correspond to a Turing pattern and provides an insight into the process. A simple analytical model was developed to explain the formation of Turing patterns: Raman lasing first starts in a single Stokes mode closest to the gain maximum; next, if the threshold power is reached and certain dispersion requirements are met, modulation instability (MI) develops for modes with multi-FSR spacing.

Studies on the biological performance of nanomedicines have been increasingly focused on the paradigm shifting role of the protein corona, which is imminently formed once the formulation is placed in a complex physiological environment. This phenomenon is predominantly studied in the context of protein adsorption science, while such interactions for water-soluble systems remain virtually unexplored. In particular, the importance of plasma protein binding is yet to be understood for pharmaceuticals designed on the basis of supramolecular architectures, which generally lack well-defined surfaces. Water-soluble ionic polyphosphazenes, clinically proven immunoadjuvants and vaccine delivery vehicles, represent an example of a system that requires supramolecular coassembly with antigenic proteins to attain an optimal immunopotentiating effect. Herein, the self-assembly behavior and stability of noncovalently bound complexes on the basis of a model antigen─hen egg lysozyme─and polyphosphazene adjuvant are studied in the presence of plasma proteins utilizing isothermal calorimetry, asymmetric flow field flow fractionation, dynamic light scattering, and size exclusion chromatography methods. The results demonstrate that although plasma proteins, such as human serum albumin (HSA), show detectable avidity to polyphosphazene, the strength of such interactions is significantly lower than that for the model antigen. Furthermore, thermodynamic parameters indicate different models of binding: entropy driven, which is consistent with the counterion release mechanism for albumin versus electrostatic interactions for lysozyme, which are characterized by beneficial enthalpy changes. In vitro protein release experiments conducted in Franz diffusion cells using enzyme-linked immunoassay detection suggest that the antigen-adjuvant complex stability is not adversely affected by the presence of the most physiologically abundant protein, which confirms the importance of the delivery modality for this immunoadjuvant. Moreover, HSA shows an unexpected stabilizing effect on complexes with high antigen load─an important consideration for further development of polyphosphazene adjuvanted vaccine formulations and their functional assessment.

Polariton thermalization is a key process in achieving light–matter Bose–Einstein condensation, spanning from solid-state semiconductor microcavities at cryogenic temperatures to surface plasmon nanocavities with molecules at room temperature. Originated from the matter component of polariton states, the microscopic mechanisms of thermalization are closely tied to specific material properties. In this work, we investigate polariton thermalization in strongly-coupled molecular systems. We develop a microscopic theory addressing polariton thermalization through electron-phonon interactions (known as exciton-vibration coupling) with low-energy molecular vibrations. This theory presents a simple analytical method to calculate the temperature-dependent polariton thermalization rate, utilizing experimentally accessible spectral properties of bare molecules, such as the Stokes shift and temperature-dependent linewidth of photoluminescence, in conjunction with well-known parameters of optical cavities. Our findings demonstrate qualitative agreement with recent experimental reports of nonequilibrium polariton condensation in both ground and excited states, and explain the thermalization bottleneck effect observed at low temperatures. This study showcases the significance of vibrational degrees of freedom in polariton condensation and offers practical guidance for future experiments, including the selection of suitable material systems and cavity designs.

Blockchain technology may the biggest achievement of cryptography of the last decade--and there are few industries craving its core ability to provide guarantees about data safety and authenticity as much [...]

Abstract: Forward osmosis is considered as an emerging technology that can compete with existing methods of desalination, purification, and concentration of natural and wastewater on the global water market. This review presents possible applications of forward osmosis, technological schemes, and the most striking case studies. The issues of forward osmosis membranes development and improvement, composition and regeneration of draw solutions, membrane fouling are considered. Special attention is paid to the problems arising during forward osmosis operation as well as to energy and economic assessment of new technology. Conclusions are drawn about the status of the commercial implementation of forward osmosis and the main barriers that stand in the way of its development.

AbstractAn integrated computational approach to drug discovery was used to identify novel potential inhibitors of the native and mutant (T315I) Bcr-Abl tyrosine kinase, the enzyme playing a key role in the pathogenesis of chronic myeloid leukemia (CML). This approach included i) design of chimeric molecules based on the 2-arylaminopyrimidine fragment, the main pharmacophore of the Abl kinase inhibitors imatinib and nilotinib used in the clinic for the CML treatment, ii) molecular docking of these compounds with the ATP-binding site of the native and mutant Abl kinase, iii) refinement of the ligand-binding poses by the quantum chemical method PM7, iv) molecular dynamics simulations of the ligand/Abl complexes, and v) prediction of the ligand/Abl binding affinity in terms of scoring functions of molecular docking, machine learning, quantum chemistry, and molecular dynamics. As a result, five top-ranking compounds able to effectively block the enzyme catalytic site were identified. According to the data obtained, these compounds exhibit close modes of binding to the Abl kinase active site that are mainly provided by hydrogen bonds and multiple van der Waals contacts. The identified compounds show high binding affinity to the native and mutant Abl kinase comparable with the one calculated for the FDA-approved kinase-targeted inhibitors imatinib, nilotinib, and ponatinib used in the calculations as a positive control. The results obtained testify to the predicted drug candidates against CML may serve as good scaffolds for the design of novel anticancer agents able to target the ATP-binding pocket of the native and mutant Abl kinase.Communicated by Ramaswamy H. Sarma

Hypoxia occurs in situations of disbalance between metabolic needs and the supply of oxygen to organs and tissues of the body. In this regard, tissue hypoxia and ischemia are essential components of the pathogenesis of many diseases. One of the promising areas of research into the mechanisms of ischemia is attempting to weaken the negative effect of hypoxia and ischemia in the brain by using a variety of techniques that activate neuroprotective mechanisms. Here, we aimed to assess the dynamics of restoration of motor activity control in an experimental model of ischemic stroke in rats (cerebral ischemia, CI) after intranasal perineural implantation of mesenchymal stem cells into the receptive field of the olfactory nerve. It was found that the perineural administration of MSCs to rats in the acute period of cerebral ischemia was accompanied by clear signs of recovery of cognitive and motor functions within 1 and 3 days after the operation. On the seventh day after ischemia modeling, rats with the introduction of MSCs had no distinctive features in the control of motor activity compared to the period before the operation in the same rats. In the hippocampus of rats after modeling ischemia, a significant decrease in the content of NO by about 50% relative to the initial level is observed after 1 day. In the hippocampus of rats in which ischemia was modeled with simultaneous intranasal administration of MSC, a significant decrease in NO content by 39% relative to the initial level was also observed after 1 day. The content of NO increases slightly, but the difference in the level of NO relative to ischemic rats was not significant. The copper content in the hippocampus in the rats of these two groups did not change. There was a tendency to increase the efficiency of the antioxidant system 1 day after ischemia in both studied groups, and this effect was more pronounced with intranasal administration of MSC.

One of the prime applications of squeezed light is enhancing the sensitivity of an interferometer below the quantum shot-noise limit, but so far, no such experimental demonstration was reported when using the optical Kerr effect. In prior setups involving Kerr-squeezed light, the role of the interferometer was merely to characterize the noise pattern. The lack of such a demonstration was largely due to the cumbersome tilting of the squeezed ellipse in phase space. Here, we present the first experimental observation of phase-sensitivity enhancement in an interferometer using Kerr squeezing.

Here, we show that the development of a conditioned defensive reflex against the context in the terrestrial snail is accompanied by a depolarization shift of the membrane potential and a decrease in the threshold of action potential generation of premotor interneurons LPa3 and RPa3. There were no further significant changes in the membrane potential of the premotor interneurons in snails after reminder (initiation of reconsolidation) with subsequent injection of either the protein synthesis inhibitor anisomycin or saline. The threshold of action potential generation of these neurons decreases after training and remains unchanged after a reminder (initiation of reconsolidation) with subsequent injection of both anisomycin and saline. No significant changes were found in the membrane and threshold potentials of serotonin-containing neurons of the pedal ganglion Pd4 and Pd2 both after training and after a reminder followed by injection of solutions.

AbstractA generative adversarial autoencoder for the rational design of potential HIV-1 entry inhibitors able to block CD4-binding site of the viral envelope protein gp120 was developed. To do this, the following studies were carried out: (i) an autoencoder architecture was constructed; (ii) a virtual compound library of potential anti-HIV-1 agents for training the neural network was formed by the concept of click chemistry allowing one to generate a large number of drug candidates by their assembly from small modular units; (iii) molecular docking of all compounds from this library with gp120 was made and calculations of the values of binding free energy were performed; (iv) molecular fingerprints of chemical compounds from the training dataset were generated; (v) training of the developed autoencoder was implemented followed by the validation of this neural network using more than 21 million molecules from the ZINC15 database. As a result, three small drug-like compounds that exhibited the high-affinity binding to gp120 were identified. According to the data from molecular docking, machine learning, quantum chemical calculations, and molecular dynamics simulations, these compounds show the low values of binding free energy in the complexes with gp120 similar to those calculated using the same computational protocols for the HIV-1 entry inhibitors NBD-11021 and NBD-14010, highly potent and broad anti-HIV-1 agents presenting a new generation of the viral CD4 antagonists. The identified CD4-mimetic candidates are suggested to present good scaffolds for the design of novel antiviral drugs inhibiting the early stages of HIV-1 infection.

AbstractThe COVID-19 pandemic in Egypt is a part of the worldwide global crisis of coronavirus 2 (SARS-CoV-2). The contagious life-threatening condition causes acute respiratory syndrome. The present study aimed to assess the compounds identified by LC-MS of the methanolic leaves extracts from three conifers trees cultivated in Egypt (Araucaria bidwillii, Araucaria. cunninghamiiand Araucaria heterophylla) via docking technique as potential inhibitor of COVID-19 virus on multiple targets; viral main protease (Mpro, 6LU7), non-structural protein-16 which is a methyl transferase (nsp16, 6W4H) and RNA dependent RNA polymerase (nsp12, 7BV2). Among the three targets, nsp16 was the best target recognized by the tested compounds as can be deduced from docking studies. Moreover, the methanolic extract of A. cunninghamiishowed the highest radical-scavenging activity using (DPPH test) with 53.7 µg/mL comparable to ascorbic acid with IC50= 46 µg/mL The anti-inflammatory potential carried using enzyme linked immunoassay showed the highest activity for A. cunninghamiiand A. bidwilliifollowed by A. heterophyllawith IC50= 23.20 ± 1.17 µg/mL, 82.83 ± 3.21 µg/mL and 221.13 ± 6.7 µg/mL, respectively (Celecoxib was used as a standard drug with IC50= 141.92 ± 4.52 µg/mL). Moreover, a molecular docking study was carried for the LC-MS annotated metabolites to validate their anti-inflammatory inhibitory effect using Celecoxib as a reference compound and showed a high docking score (−7.7 kcal/mol) for Octadecyl (E) P-coumarate and (−7.3 kcal/mol) for secoisolariciresinol rhamnoside.Communicated by Ramaswamy H. Sarma

Cocaine is a highly addictive drug that has seen a steady uptrend causing severe health problems worldwide. Currently, there are no approved therapeutics for treating cocaine use disorder; hence, there is an urgent need to identify new medications. Immunopharmacotherapeutics is a promising approach utilizing endogenous antibodies generated through active vaccination, and if properly programmed, can blunt a drug’s psychoactive and addictive effects. However, drug vaccine efficacy has largely been limited by the modest levels of antibodies induced. Herein, we explored an adjuvant system consisting of a polyphosphazene macromolecule, specifically poly[di(carboxylatoethylphenoxy)-phosphazene] (PCEP), a biocompatible synthetic polymer that was solicited for improved cocaine conjugate vaccine delivery performance. Our results demonstrated PCEP’s superior assembling efficiency with a cocaine hapten as well as with the combined adjuvant CpG oligodeoxynucleotide (ODN). Importantly, this combination led to a higher titer response, balanced immunity, successful sequestering of cocaine in the blood, and a reduction in the drug in the brain. Moreover, a PCEP–cocaine conjugate vaccine was also found to function well via intranasal administration, where its efficacy was demonstrated through the antibody titer, affinity, mucosal IgA production, and a reduction in cocaine’s locomotor activity. Overall, a comprehensive evaluation of PCEP integrated within a cocaine vaccine established an advance in the use of synthetic adjuvants in the drugs of abuse vaccine field.

Selectivity is a major issue in the development of drugs targeting pathogen aspartic proteases. Here, we explore the selectivity-determining factors by studying specifically designed malaria aspartic protease (plasmepsin) open-flap inhibitors. Metadynamics simulations are used to uncover the complex binding/unbinding pathways of these inhibitors and describe the critical transition states in atomistic resolution. The simulation results are compared with experimentally determined enzymatic activities. Our findings demonstrate that plasmepsin inhibitor selectivity can be achieved by targeting the flap loop with hydrophobic substituents that enable ligand binding under the flap loop, as such a behavior is not observed for several other aspartic proteases. The ability to estimate the selectivity of compounds before they are synthesized is of considerable importance in drug design; therefore, we expect that our approach will be useful in selective inhibitor designs against not only aspartic proteases but also other enzyme classes.

Often inspired by nature, techniques for precise droplet manipulation have found applications in microfluidics, microreactors, and water harvesting. However, a widely applicable strategy for surface modification combining simultaneous hydrophobicity and pH-sensitivity has not yet been achieved by employing environmentally friendly assembly conditions. The introduction of pH-responsive groups to an otherwise fluorinated polyphosphazene (PPZ) unlocks pH-selective droplet capture and transfer. Here, an all-aqueous layer-by-layer (LbL) deposition of polyelectrolytes is used to create unique hydrophobic coatings, endowing surfaces with the ability to sense environmental pH. The high hydrophobicity of these coatings (ultimately reaching a contact angle >120° on flat surfaces) is enabled by the formation of hydrophobic nanoscale domains and controllable by the degree of fluorination of PPZs, polyamine-binding partners, deposition pH, and coating thickness. Inspired by the hierarchical structure of rose petals, these versatile coatings reach a contact angle >150° when deposited on structured surfaces while introducing a tunable adhesivity that enables precise droplet manipulation. The films exhibited a strongly pronounced parahydrophobic rose petal behavior characterized through the contact angle hysteresis. Depositing as few as five bilayers (∼25 nm) on microstructured rather than smooth substrates resulted in superhydrophobicity with water contact angles >150° and the attenuation of the contact angle hysteresis, enabling highly controlled transfer of aqueous droplets. The pH-selective droplet transfer was achieved between surfaces with either the same microstructure and LbL film building blocks, which were assembled at different pH, or between surfaces with different microstructures coated with identical films. The demonstrated capability of these hydrophobic LbL films to endow surfaces with controlled hydrophobicity through adsorption from aqueous solutions and control the adhesion and transfer of water droplets between surfaces can be used in droplet-based microfluidics applications and water collection/harvesting.

Photobleaching is one of the basic chemical processes that occur naturally in organic molecules. In this work, we investigate the quantum dynamics of Cy 7.5 dye molecules optically coupled to Au nanorod particles and experimentally demonstrate the decrease of the photobleaching rate in this hybrid system. We discover the effect of a resonance-like behavior not observed before for any type of emitter─the photobleaching rate of the dye molecules reaches a minimum for a suitable number of molecules coupled to the nanoparticle. The manifestation of the effect is the consequence of shifts in the energy levels in the hybrid system caused by the change in the number of molecules coupled to a nanoparticle. The energy shifts are the prerequisite for the effective depopulation of the triplet level, which is responsible for the photodegradation mechanism. The discovered effect paves the way for increasing the efficiency of optoelectronic and photovoltaic devices.

The numerical method of stamp topological optimization taking into account fatigue strength is presented in the work. It is proposed to take into account the restrictions on the stress state in accordance with the curve of the dependence of the maximum stresses on the number of loading cycles in the ESO topological optimization method. An approach to the selection of the evolutionary coefficient with a step-by-step increase in the rejection coefficient is proposed when constructing an iterative scheme for the rejection of elements by the method of topological optimization. The calculation of the stamp optimal topology with a decrease in volume due to the removal and redistribution of material was carried out in the study. The new geometric model of the optimal topology stamp is based on the predicted distribution of elements with a minimum stress level. The verification calculation of the stress state of the stamp of optimal topology with an assessment of fatigue strength was carried out in the work. The numerical calculation was carried out using the finite element method in the Ansys software package. The minimized stamp volume decreased by 35% according to the calculation results. The results of the study can be further applied in the development of topological optimization methods and in the design of stamping tools of optimal topology.

In early-stage drug discovery, the hit-to-lead optimization (or “hit expansion”) stage entails starting from a newly identified active compound and improving its potency or other properties. Traditionally, this process relies on synthesizing and evaluating a series of analogues to build up structure–activity relationships. Here, we describe a computational strategy focused on kinase inhibitors, intended to expedite the process of identifying analogues with improved potency. Our protocol begins from an inhibitor of the target kinase and generalizes the synthetic route used to access it. By searching for commercially available replacements for the individual building blocks used to make the parent inhibitor, we compile an enumerated library of compounds that can be accessed using the same chemical transformations; these huge libraries can exceed many millions─or billions─of compounds. Because the resulting libraries are much too large for explicit virtual screening, we instead consider alternate approaches to identify the top-scoring compounds. We find that contributions from individual substituents are well described by a pairwise additivity approximation, provided that the corresponding fragments position their shared core in precisely the same way relative to the binding site. This key insight allows us to determine which fragments are suitable for merging into single new compounds and which are not. Further, the use of pairwise approximation allows interaction energies to be assigned to each compound in the library without the need for any further structure-based modeling: interaction energies instead can be reliably estimated from the energies of the component fragments, and the reduced computational requirements allow for flexible energy minimizations that allow the kinase to respond to each substitution. We demonstrate this protocol using libraries built from six representative kinase inhibitors drawn from the literature, which target five different kinases: CDK9, CHK1, CDK2, EGFRT790M, and ACK1. In each example, the enumerated library includes additional analogues reported by the original study to have activity, and these analogues are successfully prioritized within the library. We envision that the insights from this work can facilitate the rapid assembly and screening of increasingly large libraries for focused hit-to-lead optimization. To enable adoption of these methods and to encourage further analyses, we disseminate the computational tools needed to deploy this protocol.

In this Letter, we give a new, to the best of our knowledge, perspective on the origin of light coherence in lasers. We demonstrate that a coherence appears below the lasing threshold and manifests itself as long-range correlations between polarizations of active medium atoms. These correlations contribute to the formation of a collective state of atomic polarizations and electromagnetic field modes, which interacts more effectively with the active medium and lases when pumping exceeds the lasing threshold. We demonstrate that inhibiting these atomic correlations leads to the destruction of the collective state and suppression of lasing. The obtained results open up new ways to control coherence.

The recent progress in nanotechnology1,2and single-molecule spectroscopy3–5paves the way for emergent cost-effective organic quantum optical technologies with potential applications in useful devices operating at ambient conditions. We harness a π-conjugated ladder-type polymer strongly coupled to a microcavity forming hybrid light–matter states, so-called exciton-polaritons, to create exciton-polariton condensates with quantum fluid properties. Obeying Bose statistics, exciton-polaritons exhibit an extreme nonlinearity when undergoing bosonic stimulation6, which we have managed to trigger at the single-photon level, thereby providing an efficient way for all-optical ultrafast control over the macroscopic condensate wavefunction. Here, we utilize stable excitons dressed with high-energy molecular vibrations, allowing for single-photon nonlinear operation at ambient conditions. This opens new horizons for practical implementations like sub-picosecond switching, amplification and all-optical logic at the fundamental quantum limit.

AbstractA computational approach to in silicodrug discovery was carried out to identify small drug-like compounds able to show structural and functional mimicry of the high affinity ligand X77, potent non-covalent inhibitor of SARS-COV-2 main protease (MPro). In doing so, the X77-mimetic candidates were predicted based on the crystal X77-MProstructure by a public web-oriented virtual screening platform Pharmit. Models of these candidates bound to SARS-COV-2 MProwere generated by molecular docking, quantum chemical calculations and molecular dynamics simulations. At the final point, analysis of the interaction modes of the identified compounds with MProand prediction of their binding affinity were carried out. Calculation revealed 5 top-ranking compounds that exhibited a high affinity to the active site of SARS-CoV-2 MPro. Insights into the ligand − MPromodels indicate that all identified compounds may effectively block the binding pocket of SARS-CoV-2 MPro, in line with the low values ​​of binding free energy and dissociation constant. Mechanism of binding of these compounds to MProis mainly provided by van der Waals interactions with the functionally important residues of the enzyme, such as His-41, Met-49, Cys-145, Met-165, and Gln-189 that play a role of the binding hot spots assisting the predicted molecules to effectively interact with the MProactive site. The data obtained show that the identified X77-mimetic candidates may serve as good scaffolds for the design of novel antiviral agents able to target the active site of SARS-CoV-2 MPro.Communicated by Ramaswamy H. Sarma

ABSTRACTCurrent human papillomavirus (HPV) vaccines provide substantial protection against the most common HPV types responsible for oral and anogenital cancers, but many circulating cancer-causing types remain for which vaccine coverage is lacking. In addition, all current HPV vaccines rely on aluminum salt-based adjuvant formulations that function through unclear mechanisms with few substitutes available. In an effort to expand the toolbox of available adjuvants suitable for HPV vaccines, we compared the immunogenicity of the RG1-VLP (virus-like particle) vaccine in BALB/c mice when formulated with either the aluminum hydroxide adjuvant Alhydrogel or the novel polyphosphazene macromolecular adjuvant poly[di (carboxylatoethylphenoxy) phosphazene] (PCEP). PCEP-formulated RG1-VLPs routinely outperformed VLP/Alhydrogel in several measurements of VLP-specific humoral immunity, including consistent improvements in the magnitude of antibody (Ab) responses to both HPV16-L1 and the L2 RG1 epitope as well as neutralizing titers to HPV16 and cross-neutralization of pseudovirion (PsV) types HPV18 and HPV39. Dose-sparing studies indicated that RG1-VLPs could be reduced in dose by 75% and the presence of PCEP ensured activity comparable to a full VLP dose adjuvanted by Alhydrogel. In addition, levels of HPV16-L1 and -L2-specific Abs were achieved after two vaccinations with PCEP as adjuvant that were equivalent to or greater than levels achieved with three vaccinations with Alhydrogel alone, indicating that the presence of PCEP resulted in accelerated immune responses that could allow for a decreased dose schedule. Given the extensive clinical track record of polyphosphazenes, these data suggest that substitution of alum-based adjuvants with PCEP for the RG1-VLP vaccine could lead to rapid seropositivity requiring fewer boosts, the dose-sparing of commercial VLP-based vaccines, and the establishment of longer-lasting humoral responses to HPV.

Chronic pain affects approximately 100 million Americans and only a minority of patients experience satisfactory relief of their pain with currently available pharmaceutics. One type of chronic pain is caused by direct injury to the nerve called neuropathic pain, which affects ~10% of the overall population. Despite the prevalence, the underlying mechanisms of neuropathic pain are not well-defined, and better understanding of the mechanisms that promote central sensitization after injury could lead to better treatment of this condition. Notably, a recent meta-analysis of microarray studies of pain-related genes demonstrated a remarkable enrichment of genes related to the complement system activation. Among the complement products, C5a and its receptor C5aR1 seem to be especially important in the pathogenesis of neuropathic pain. However, it is not well understood how C5a/C5aR1 signaling contributes to pain amplification in the spinal cord and which cells are involved. Here, we used immunohistochemistry (IHC) to examine which cells within the spinal cord express C5aR1. Our data show that C5aR1 is expressed primarily in microglia and astrocytes, but not in neurons. To further investigate the function of C5aR1, we have generated two mouse lines with C5aR1 deletion specifically in microglia and astrocytes, respectively to test the roles of C5aR1 in these cell types during neuropathic pain. Our data suggest that C5aR1 expressed in microglia is essential for the initiation of neuropathic pain. Collectively, these results provide a new mechanistic insight into the role of C5a/C5aR1 signaling in neuropathic pain. Research reported in this presentation is supported by the NIH/NIGMS grant T34GM141143 (K.C.), NIH/NINDS grant R01NS131189 (Y.M.U.), the University of Iowa (UI) Office of the Vice President for Research, Graduate College, College of Liberal Arts and Sciences, Department of Biology, and Office of the Provost (K.C.).

Silver sulfide nanoparticles (Ag2S‐NP) hold promise for various optical‐based biomedical applications, such as near‐infrared fluorescence (NIRF) imaging, photoacoustics (PA), and photothermal therapy (PTT). However, their NIR absorbance is relatively low, and previous formulations are synthesized using toxic precursors under harsh conditions and are not effectively cleared due to their large size. Herein, sub‐5 nm Ag2S‐NP are synthesized and encapsulated in biodegradable, polymeric nanoparticles (AgPCPP). All syntheses are conducted using biocompatible, aqueous reagents under ambient conditions. The encapsulation of Ag2S‐NP in polymeric nanospheres greatly increases their NIR absorbance, resulting in enhanced optical imaging and PTT effects. AgPCPP nanoparticles exhibit potent contrast properties suitable for PA and NIRF imaging, as well as for computed tomography (CT). Furthermore, AgPCPP nanoparticles readily improve the conspicuity of breast tumors in vivo. Under NIR laser irradiation, AgPCPP nanoparticles significantly reduce breast tumor growth, leading to prolonged survival compared to free Ag2S‐NP. Over time, AgPCPP retention in tissues gradually decreases, without any signs of acute toxicity, providing strong evidence of their safety and biodegradability. Therefore, AgPCPP may serve as a “one‐for‐all” theranostic agent that degrades into small components for excretion after fulfilling diagnostic and therapeutic tasks, offering good prospects for clinical translation. Ultrasmall silver sulfide nanoparticles are encapsulated within biodegradable PCPP polymers that offer size tunability. This innovative design enables the imaging of breast cancer through multiple modalities, while significantly improving the efficacy of photothermal treatment. As the polymeric nanoparticles gradually break down into harmless byproducts, the small metal cores are efficiently cleared from the body.

Abstract: The main problems associated with the operation of reverse osmosis facilities in the treatment of groundwater for drinking water are considered and the possibilities of reducing the concentrate consumption are studied. The existing solutions for reducing the consumption of concentrate using reagent and evaporation techniques are described. The presented article is devoted to the investigation of possibilities to remove calcium carbonate from concentrate due to calcium deposition on “seed” crystals. A new technique for reducing concentrate flow is presented that consists of the operation of a membrane unit in circulation mode whereby concentrate is circulated through a “seed” reactor. Calcium and carbonate ions deposit on the seed crystals thus reducing the scaling hazard and total dissolved solid (TDS) value. A water treatment flow diagram is presented and technical parameters of membrane facilities are determined at each stage that allow one to calculate the entire technological scheme. The product flow on each membrane stage is calculated, scaling rates and calcium carbonate deposition rates are evaluated; caustic consumption and number of membrane facilities at each stage are determined. An experimental technique to determine the amount of hardness removed from the concentrate and the minimal volume of concentrate that could be reached per day is described. The main dependences are obtained and presented, which make it possible to determine the costs of electricity and reagents, types of membranes and volumes of concentrate, the rates of accumulation of sediment on the membranes, and the efficiency of removing hardness ions from water during the operation of the third-stage setup in the circulation mode.

Proteolysis-targeting chimaeras (PROTACs) are molecules that combine a target-binding warhead with an E3 ligase-recruiting moiety; by drawing the target protein into a ternary complex with the E3 ligase, PROTACs induce target protein degradation. While PROTACs hold exciting potential as chemical probes and as therapeutic agents, development of a PROTAC typically requires synthesis of numerous analogs to thoroughly explore variations on the chemical linker; without extensive trial and error, it is unclear how to link the two protein-recruiting moieties to promote formation of a productive ternary complex. Here, we describe a structure-based computational method for evaluating the suitability of a given linker for ternary complex formation. Our method uses Rosetta to dock the protein components and then builds the PROTAC from its component fragments into each binding mode; complete models of the ternary complex are then refined. We apply this approach to retrospectively evaluate multiple PROTACs from the literature, spanning diverse target proteins. We find that modeling ternary complex formation is sufficient to explain both activity and selectivity reported for these PROTACs, implying that other cellular factors are not key determinants of activity in these cases. We further find that interpreting PROTAC activity is best approached using an ensemble of structures of the ternary complex rather than a single static conformation and that members of a structurally conserved protein family can be recruited by the same PROTAC through vastly different binding modes. To encourage adoption of these methods and promote further analyses, we disseminate both the computational methods and the models of ternary complexes.

Abstract: Clinically, the use of photo-activated polymer-based dental composites is the preferred method to restore carious teeth due to their esthetics and ease of application. However, the longevity of these resin-based composite tooth restorations can be compromised by the sensitivity of the bonded interface between the composite and the tooth surface. The objective of the current study was to modify the tooth surface with novel fluorinated polyphosphazenes (PPZs), thereby improving the stability of the interface. Binding isotherms of PPZs with collagen (CLG) and hydroxyapatite (HA), two of the primary components of teeth, were established and indicate significant and stable adsorption to the surfaces of these materials. PPZs were also shown to protect CLG against acidic dissolution in a model system. A composite material consisting of the fluorinated polymer and CLG demonstrated three-dimensional stability and significant hydrophobicity. Additionally, no hemolytic activity was observed when evaluated using a porcine red blood cells (RBC) assay. Bovine dentin treated with PPZs demonstrated increased contact angle (hydrophobicity) compared with control samples and resisted fluid penetration when assessed using a dye penetration study. Finally, microhardness evaluation of bovine dentin treated with PPZs and exposed to an acidic challenge showed that treated dentin resisted demineralization. The hardness of the untreated control was significantly reduced after exposure when compared with the PPZ-treated samples. This study represents a novel approach to overcoming the current limitations of composite restorations. These results are promising to improve the longevity of composite dental restorations and may have wider use in sealants, varnishes, and other dental applications. Lay Summary: Tooth decay remains a prevalent problem worldwide. Polymer-based composites are the most frequently used tooth restorative used in the clinic. The longevity of these fillings is limited due to conditions in the mouth that can weaken the adhesive used to bond the composite to the natural tooth. The current study uses novel polyphosphazenes (PPZs), hybrid organic-inorganic macromolecules with tunable hydrophilic-hydrophobic properties to coat the tooth surface to achieve better compatibility with the adhesive, thereby improving the longevity of the restoration. Results indicate that PPZs have significant and stable adsorption onto teeth, which may lead to a more stable bonded interface.

Two well-defined synthetic polyphosphazene immunoadjuvants, PCPP and PCEP, were studied for their ability to potentiate the immune response to the hepatitis C virus (HCV) E2 glycoprotein antigen in vivo. We report that PCEP induced significantly higher serum neutralization and HCV-specific IgG titers in mice compared to other adjuvants used in the study: PCPP, Alum, and Addavax. PCEP also shifted the response toward the desirable balanced Th1/Th2 immunity, as evaluated by the antibody isotype ratio (IgG2a/IgG1). The in vivoresults were analyzed in the context of antigen–adjuvant molecular interactions in the system and in vitroimmunostimulatory activity of formulations. Asymmetric flow field flow fractionation (AF4) and dynamic light scattering (DLS) analysis showed that both PCPP and PCEP spontaneously self-assemble with the E2 glycoprotein with the formation of multimeric water-soluble complexes, which demonstrates the role of polyphosphazene macromolecules as vaccine delivery vehicles. Intrinsic in vitroimmunostimulatory activity of polyphosphazene adjuvants, which was assessed using a mouse macrophage cell line, revealed comparable activities of both polymers and did not provide an explanation of their in vivoperformance. However, PCEP complexes with E2 displayed greater stability against agglomeration and improved in vitroimmunostimulatory activity compared to those of PCPP, which is in line with superior in vivoperformance of PCEP. The results emphasize the importance of often neglected antigen–polyphosphazene self-assembly mechanisms in formulations, which can provide important insights on their in vivobehavior and facilitate the establishment of a structure–activity relationship for this important class of immunoadjuvants.

We propose a simple, highly scalable, and very efficient scheme for coherent combining of tiled aperture arrays. The scheme relies on changing the beam phasing paradigm from the commonly used in-phase pattern to the out-of-phase pattern (interleaved 0/π phases in the neighboring channels) and using an additional simple combining stage (a beamsplitter). In a proof-of-concept experiment with a one-dimensional fiber array, we achieved 89% of the power in the main combined beam. In numerical modeling, we found optimal conditions leading to 98% efficiency for an unlimited number of channels and arbitrary small initial aperture fill factors. The scheme is highly resistant to the effect of sub-aperture clipping and suitable for combining ultrashort pulses.

We theoretically study the role of strong coupling between an organic J-aggregated chromophore and a plasmonic nanostructure in the process of photobleaching suppression. We take into account the influence of vibrational degrees of freedom of nuclei in the molecules of J-aggregates in the Born–Markov approximation. We then show that in the strong coupling regime in this system, the stability of the J-aggregated chromophore increases by an order of magnitude. We also show that there is an optimal value of red detuning between the plasmon resonance frequency and the frequency of the dipole transition in the J-aggregate, for which the photobleaching suppression is most pronounced. We find this optimal value at different Rabi frequencies. Our results clarify the role of strong coupling between a plasmon structure near field and a molecular dipole moment in the process of photobleaching suppression and they pave the way for control of a chemical reaction in the vicinity of a plasmonic nanostructure.

An algorithm has been demonstrated for simultaneously measuring the phase and arrival time of optical pulses relative to pulses in a reference channel using one detector array. Based on this algorithm, a simple optoelectronic pulse phase and arrival time stabilisation scheme has been designed for operation in a coherent beam combining fibre system for ultrashort pulses (including chirped ones). We have studied the performance of the stabilisation scheme. In particular, we have reached a phase measurement rate of 25 000 cps, demonstrated an ? 2 kHz limiting phase stabilisation frequency in a feedback loop, and obtained an arrival time measurement accuracy of ? 5 % of the transform-limited pulse duration at a measurement rate of 5 cps. In experiments concerned with coherent beam combining for two channels of a pulsed fibre system at a wavelength of 1030 nm, we have demonstrated phase stabilisation with an accuracy better than ?/100 and delay setting accuracy of 10 fs at a transform-limited pulse duration of ? 200 fs and obtained 94 % beam combining efficiency.

Propagation and amplification of intense coherent laser pulses in a multicore fiber of 24 weakly coupled cores arranged in the form of seven close-packed hexagons were studied. Exact stable analytical solutions are found for the out-of-phase mode, which describes the coherent propagation of wave beams and temporal soliton solutions in such fibers. Their stability is demonstrated. The analytical results are confirmed by the direct numerical simulation of the wave equation.

In this theoretical work, the performances of ultrafast, carrier-envelope-phase-stable (CEP), mid-IR optical parametric chirped pulse amplification (OPCPA) systems were compared in two different amplification schemes. In the “idler scheme” the mid-IR pulse (idler) is produced in the first difference frequency generation stage of the OPCPA chain and then amplified in the following stages. In the “signal scheme,” the supercontinuum seed is amplified in the OPCPA chain and the mid-IR pulse is generated in the last amplifier stage. According to our results, the idler has higher energy and better energy stability in the idler scheme, while in the signal scheme the signal has the better characteristics in energy and stability. The CEP noise due to the pump intensity fluctuations was found to be lower in the signal scheme. Additionally, chirp optimization revealed that the peak power of the compressed idler and signal pulses at the output of the system is considerably higher if the chirp of the input signal pulse is positive.

It was previously shown that both associative learning and the formation of long-term sensitization led to the increase in excitability of premotor interneurons of the defensive behavior of terrestrial snail Helix lucorum. In the present study, we analyzed the role of intracellular calcium ions in the maintenance of increased excitability in premotor interneurons of terrestrial snail after the formation of a conditioned defensive reflex. It was shown that the increase of the intracellular Ca2+concentration after adding caffeine to the solution washing the nervous system of the mollusk led to a decrease of the threshold of action potential and to an increase of the critical level of depolarization without a change of the membrane potential of premotor interneurons in both intact and trained snails. The decrease of the intracellular Ca2+concentration in premotor interneurons by the intracellular injection of (ethylene glycol-bis (2-aminoethylether)-N, N, N, N-tetraacetic acid) (EGTA) resulted in a significant increase of the threshold of generation of the action potential in intact snails. But the values of threshold of generation of the action potential in trained snails after injection of EGTA did not significantly differ from the values of studied parameters before injection. After application of the membrane-penetrating chelator, BAPTA-AM, the changes in the membrane and threshold potentials of premotor interneurons of intact and trained snails were not observed. Our results demonstrated that both the increase and decrease of intracellular Ca2+concentration were not involved in maintaining the changes of membrane characteristics of premotor interneurons observed after associative learning.

Abstract: Knowledge of the mechanism of deposition of sparingly soluble salts (scaling) in reverse osmosis membrane devices is extremely important for the selection of means of controlling the scaling and increasing the recovery. This study has made it possible to take a fresh look at the mechanism of scaling and the role of antiscalants in the inhibition of this process. The development of the experimental procedure is based on the idea that the first phase of crystallization—nucleation—is homogeneous; that is, it occurs in the “dead” areas in the bulk of the concentrate at high values of calcium carbonate supersaturation. After formation, the crystals are removed from the “dead” areas and deposited on the membrane surface, like other suspended particles contained in the feed water. The paper also presents the results of a study of the adsorption of polymeric antiscalants on crystal surfaces during nucleation and crystal growth on the membrane. The experimentally revealed relations of the adsorption rates of antiscalants to the antiscalant dose, the calcium carbonate formation rate, the nucleation rate, and the total surface of the seed crystals formed are presented. An experimental procedure is described that makes it possible to determine the concentration of dissolved salts in the dead areas and calculate the supersaturation values corresponding to the onset of crystallization from antiscalant-free water and water in the presence of scale inhibitors in various amounts.

A mechanism for self-compression of laser pulses in a multicore fiber on the basis of nonlinear combining of radiation from many cores, surrounding the central core in a ring and its trapping into the central core in a chirp-free and pedestal-free soliton-like pulse, is proposed. It is shown that the compression ratio is weakly dependent on the energy and the number of cores in the fiber and approximately equal to 6 with an almost 100% energy efficiency. The compression ratio can be increased to 40 with an efficiency of more than 50% by using additional compression of longer pulses with approximately the same energy. The possibility of a 38-fold compression of a laser pulse to a duration of 15 fs with a pulse energy of 4 nJ in the fiber with realistic parameters was demonstrated numerically.

Knowledge of the scaling mechanism makes it possible to develop effective means to control scaling and improve the membrane performance, increasing the recovery. This paper presents new approaches to the study of the mechanism of scaling in the presence of polymeric inhibitors (antiscalants); the adsorption of antiscalant molecules on the crystal and membrane surfaces has been investigated. The relations of the antiscalant adsorption rates to the antiscalant dose and the calcium carbonate scaling rate have been revealed. For the first time, the inhibition process was “visualized” by using a fluorescent antiscalant containing a fluorescent moiety—a copolymer of N-allyl-4-methoxy-1,8-naphthalamide and acrylic acid (PAA-F1). The examination of the surfaces of crystals and membranes by scanning electron and fluorescence microscopy showed new unexpected results: the antiscalant is adsorbed on the membrane surface and on the surface of calcite crystals formed. Fluorescence turned out to be more intense and noticeable on the surface of crystal faces than inside the crystal. During the nucleation phase, the “dark” part of the crystal lattice is formed and then begins to be covered with a “luminous” layer of the fluorescent antiscalant, which blocks further crystal growth. During experiments with antiscalant solutions in distilled water, the antiscalant was found to be adsorbed on the membrane surface in the absence of calcium ions. In experiments in which the antiscalant was added into the original tap water, it was adsorbed on the surface of the resulting crystals, not on the membrane. The visualization of the crystal growth inhibition process opens up new possibilities for studying the mechanism of scaling and developing of new technologies to control scaling.

Optimization of parameters of the corrugated shell aims to achieve its minimum weight while keeping maximum stiffness ability. How an introduction of functionally graded corrugations resulted in improved efficiency of this thin-walled structure is demonstrated. The corrugations are graded varying their pitch. The effect of variation in pitch is studied. Homogenization approach gives explicit expressions to calculate the equivalent shell properties. Then well-elaborate methods of optimal design theory are used. The illustrative examples for hydrostatic load demonstrate a high efficiency of the used method.

We consider the transition from the description of a closed quantum system consisting of an open quantum system and a reservoir to the description of the open quantum system alone by eliminating the reservoir degrees of freedom by averaging over them. An approach based on the Lindblad master equation for the density matrix is used. A general scheme is developed for deriving the Lindblad superoperator that emerges after averaging the von Neumann equation over the reservoir degrees of freedom. This scheme is illustrated with the cases of radiation of a two-level atom into free space and the dynamics of the transition of a two-level atom from a pure state to a mixed state due to interaction with a dephasing reservoir. Special attention is paid to the open system consisting of several subsystems each of which independently interacts with the reservoir. In the case of noninteracting subsystems, the density matrix is a tensor product of the subsystem density matrices, and the Lindblad superoperator of the system is a sum of Lindblad superoperators of those subsystems. The interaction between the subsystems results not only in the emergence of the corresponding term in the Hamiltonian of the combined system but also in the nonadditivity of the Lindblad superoperators. This is often overlooked in modern literature, possibly leading, as is shown in this methodological note, to serious errors; for example, the second law of thermodynamics could be violated.

We present a theoretical description of different types of accretion disks and jets near supermassive black holes (SMBHs) that can be observed in the (sub)millimeter wave band. Special attention is paid to the possible formation of the shadow of a black hole illuminated by an accretion disk or a jet. We suggest a simple criterion for identifying such a shadow in current and planned SMBH observations using very long baseline interferometry (VLBI). As an example, we propose a number of potential SMBH candidates satisfying this criterion for observations with the future Millimetron space observatory in the VLBI regime and with the Event Horizon Telescope.

A method for the construction of periodic dual wavelet frames is provided. The method is algorithmic, it allows to construct dual frames based on any suitable generating function. As a corollary, we describe a wide class of periodic functions which can be extended to a wavelet frame.