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Current 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.

The inclusion of fluorine motifs in drugs and drug delivery systems is an established tool for modulating their biological potency. Fluorination can improve drug specificity or boost the vehicle’s ability to cross cellular membranes. However, the approach has yet to be applied to vaccine adjuvants. Herein, the synthesis of fluorinated bioisostere of a clinical stage immunoadjuvant—poly[di(carboxylatophenoxy)phosphazene], PCPP—is reported. The structure of water-soluble fluoropolymer—PCPP-F, which contains two fluorine atoms per repeat unit—was confirmed using 1H, 31P and 19F NMR, and its molecular mass and molecular dimensions were determined using size-exclusion chromatography and dynamic light scattering. Insertion of fluorine atoms in the polymer side group resulted in an improved solubility in acidic solutions and faster hydrolytic degradation rate, while the ability to self-assemble with an antigenic protein, lysozyme—an important feature of polyphosphazene vaccine adjuvants—was preserved. In vivo assessment of PCPP-F demonstrated its greater ability to induce antibody responses to Hepatitis C virus antigen when compared to its non-fluorinated counterpart. Taken together, the superior immunoadjuvant activity of PCPP-F, along with its improved formulation characteristics, demonstrate advantages of the fluorination approach for the development of this family of macromolecular vaccine adjuvants.

Ebolavirus (EBOV) infection in humans is a severe and often fatal disease, which demands effective interventional strategies for its prevention and treatment. The available vaccines, which are authorized under exceptional circumstances, use viral vector platforms and have serious disadvantages, such as difficulties in adapting to new virus variants, reliance on cold chain supply networks, and administration by hypodermic injection. Microneedle (MN) patches, which are made of an array of micron-scale, solid needles that painlessly penetrate into the upper layers of the skin and dissolve to deliver vaccines intradermally, simplify vaccination and can thereby increase vaccine access, especially in resource-constrained or emergency settings. The present study describes a novel MN technology, which combines EBOV glycoprotein (GP) antigen with a polyphosphazene-based immunoadjuvant and vaccine delivery system (poly[di(carboxylatophenoxy)phosphazene], PCPP). The protein-stabilizing effect of PCPP in the microfabrication process enabled preparation of a dissolvable EBOV GP MN patch vaccine with superior antigenicity compared to a non-polyphosphazene polymer-based analog. Intradermal immunization of mice with polyphosphazene-based MN patches induced strong, long-lasting antibody responses against EBOV GP, which was comparable to intramuscular injection. Moreover, mice vaccinated with the MN patches were completely protected against a lethal challenge using mouse-adapted EBOV and had no histologic lesions associated with ebolavirus disease.

The in vivo potency of polyphosphazene immunoadjuvants is inherently linked to the ability of these ionic macromolecules to assemble with antigenic proteins in aqueous solutions and form physiologically stable supramolecular complexes. Therefore, in-depth knowledge of interactions in this biologically relevant system is a prerequisite for a better understanding of mechanism of immunoadjuvant activity. Present study explores a self-assembly of polyphosphazene immunoadjuvant—PCPP and a model antigen—lysozyme in a physiologically relevant environment—saline solution and neutral pH. Three analytical techniques were employed to characterize reaction thermodynamics, water-solute structural organization, and supramolecular dimensions: isothermal titration calorimetry (ITC), water proton nuclear magnetic resonance (wNMR), and dynamic light scattering (DLS). The formation of lysozyme–PCPP complexes at near physiological conditions was detected by all methods and the avidity was modulated by a physical state and dimensions of the assemblies. Thermodynamic analysis revealed the dissociation constant in micromolar range and the dominance of enthalpy factor in interactions, which is in line with previously suggested model of protein charge anisotropy and small persistence length of the polymer favoring the formation of high affinity complexes. The paper reports advantageous use of wNMR method for studying protein-polymer interactions, especially for low protein-load complexes.

Self-assembly of ionically charged small molecule drugs with water-soluble biodegradable polyelectrolytes into nano-scale complexes can potentially offer a novel and attractive approach to improving drug solubility and prolonging its half-life. Nanoassemblies of quisinostat with water-soluble PEGylated anionic polyphosphazene were prepared by gradient-driven escape of solvent resulting in the reduction of solvent quality for a small molecule drug. A study of binding, analysis of composition, stability, and release profiles was conducted using asymmetric flow field flow fractionation (AF4) and dynamic light scattering (DLS) spectroscopy. Potency assays were performed with WM115 human melanoma and A549 human lung cancer cell lines. The resulting nano-complexes contained up to 100 drug molecules per macromolecular chain and displayed excellent water-solubility and improved hemocompatibility when compared to co-solvent-based drug formulations. Quisinostat release time (complex dissociation) at near physiological conditions in vitro varied from 5 to 14 days depending on initial drug loading. Multimeric complexes displayed dose-dependent potency in cell-based assays and the results were analyzed as a function of complex concentration, as well as total content of drug in the system. The proposed self-assembly process may present a simple alternative to more sophisticated delivery modalities, namely chemically conjugated prodrug systems and nanoencapsulation-based formulations.

Achieving intracellular delivery of protein therapeutics within cells remains a significant challenge. Although custom formulations are available for some protein therapeutics, the development of non-toxic delivery systems that can incorporate a variety of active protein cargo and maintain their stability, is a topic of great relevance. This study utilized ionic polyphosphazenes (PZ) that can assemble into supramolecular complexes through non-covalent interactions with different types of protein cargo. We tested a PEGylated graft copolymer (PZ-PEG) and a pyrrolidone containing linear derivative (PZ-PYR) for their ability to intracellularly deliver FITC-avidin, a model protein. In endothelial cells, PZ-PYR/protein exhibited both faster internalization and higher uptake levels than PZ-PEG/protein, while in cancer cells both polymers achieved similar uptake levels over time, although the internalization rate was slower for PZ-PYR/protein. Uptake was mediated by endocytosis through multiple mechanisms, PZ-PEG/avidin colocalized more profusely with endo-lysosomes, and PZ-PYR/avidin achieved greater cytosolic delivery. Consequently, a PZ-PYR-delivered anti-F-actin antibody was able to bind to cytosolic actin filaments without needing cell permeabilization. Similarly, a cell-impermeable Bax-BH3 peptide known to induce apoptosis, decreased cell viability when complexed with PZ-PYR, demonstrating endo-lysosomal escape. These biodegradable PZs were non-toxic to cells and represent a promising platform for drug delivery of protein therapeutics.

Water-soluble polyphosphazene polyacids, such as poly[di(carboxylatophenoxy)phosphazene] (PCPP), have been of significant interest due to their unique immunoadjuvant and vaccine delivery properties. We report that PCPP can spontaneously self-assemble into intermolecular complexes with common formulation excipients − polyethers in aqueous solutions at neutral pH through the establishment of hydrogen bonds. The resulting advanced PCPP delivery modalities can range from macromolecular assemblies at the nanoscale level to physically cross-linked hydrogels and the physical state can be modulated through varying polymer ratios and molecular weight of polyether. It has been demonstrated that such macromolecular complexes maintain protein-binding ability − a key characteristics of the delivery system. Importantly, the non-covalent modification of PCPP immunoadjuvant with polyethers introduces pH dependent membrane disruptive activity, which is not characteristic for PCPP itself, and is typically correlated to the ability of macromolecular carrier to facilitate endosomal escape. This can potentially affect the mechanism of immunoadjuvant action displayed by PCPP, afford means for its fine-tuning, as well as provide important insights for understanding the relationship between fundamental physico-chemical characteristics of polyphosphazene immunoadjuvants and their activity in vivo.

This paper gives an overview over all currently available data sets for the European Long-term Ecosystem Research (eLTER) monitoring site Gesäuse-Johnsbachtal. The site is part of the LTSER platform Eisenwurzen in the Alps of the province of Styria, Austria. It contains both protected (National Park Gesäuse) and non-protected areas (Johnsbachtal). Although the main research focus of the eLTER monitoring site Gesäuse-Johnsbachtal is on inland surface running waters, forests and other wooded land, the eLTER whole system (WAILS) approach was followed in regard to the data selection, systematically screening all available data in regard to its suitability as eLTER’s Standard Observations (SOs). Thus, data from all system strata was included, incorporating Geosphere, Atmosphere, Hydrosphere, Biosphere and Sociosphere. In the WAILS approach these SOs are key data for a whole system approach towards long term ecosystem research. Altogether, 54 data sets have been collected for the eLTER monitoring site Gesäuse-Johnsbachtal and included in the Dynamical Ecological Information Management System – Site and Data Registry (DEIMS-SDR), which is the eLTER data platform. The presented work provides all these data sets through dedicated data repositories for FAIR use. This paper gives an overview on all compiled data sets and their main properties. Additionally, the available data are evaluated in a concluding gap analysis with regard to the needed observation data according to WAILS, followed by an outlook on how to fill these gaps.

Objetivo: analizar el efecto que tienen las citas provenientes de revistas de la colección Emerging Sources Citation Index en el valor del Factor de Impacto de las revistas latinoamericanas incluidas en los Journal Citation Reports. Método: se emplearon 241 revistas de la edición 2020, que representan el 2% del total de las colecciones de Ciencias Sociales y Exactas del Journal Citation Reports. Para el desarrollo de la investigación se sistematizó la información de cada revista, recogiendo datos descriptivos de utilidad para cada una de las fases de análisis. A partir de las citas que aportan las revistas Emerging Sources Citation Index, se realizó un nuevo cálculo del Factor de Impacto eliminando de la fórmula las citas provenientes de estas revistas, para establecer conclusiones que aporten al debate sobre el efecto real y relevancia de las revistas de esta colección y la relevancia, comparando este resultado con el Factor de Impacto sin autocitas. Se revisó además la literatura relacionada con los indicadores bibliométricos, especialmente el Factor de Impacto, sus distintas metodologías de cálculo, sus implicaciones y repercusiones y cómo estas contribuyen al debate sobre su uso como medida de evaluación. Resultados: aunque las citas emitidas por las revistas Emerging Sources Citation Index afectan en general el valor del Factor de Impacto en gran parte de la muestra seleccionada, no se observaron descensos significativos. El mayor porcentaje de citas emitidas por la colección emergente proviene de Brasil, con el mayor número de revistas en el Journal Citation Reports y se observa con mayor claridad su efecto en ámbitos de Ciencias Exactas y en revistas Q4 del Journal Citation Reports. Conclusiones: la situación que propician las revistas emergentes y el número de citas que aportan constituye un valor añadido, que en el futuro puede explotarse para el mejoramiento de las propias revistas y la visibilidad de la región dentro de una fuente tan importante como Web of Science, además de contar con mayor número de revistas en la colección central para la evaluación de la investigación.

Los fenómenos sociotecnológicos se caracterizan por integrar aspectos sociales, técnicos y tecnológicos. Este tipo de fenómenos están compuestos por personas que pretenden alcanzar una serie de objetivos por medio de herramientas tecnológicas. Para entender el comportamiento dinámico de estos fenómenos, se hace necesario realizar procesos de modelamiento y simulación que integren los múltiples elementos y relaciones que los componen. El objetivo de este documento fue explicar el campo teórico del modelamiento y la simulación de los fenómenos sociotecnológicos desde un proceso de revisión sistemática de la literatura, la aplicación de la metodología de vigilancia tecnológica UNE 166006:2011 y minería de datos mediante el software Vantage Point. Como una de las conclusiones identificadas se menciona que este campo está abierto a la investigación que desde Colombia y Latinoamérica se pueda hacer.

Over the last four decades, a large number of studies have been published on pillared interlayered clays (PILCs) used as adsorbent materials and catalysts or supports for transition metals in heterogeneous catalysis. Particularly, PILCs have been used for water treatment through advanced oxidation processes (AOPs) to remove organic pollutants. They have also been studied in various chemical and environmental processes. Because of the growing interest in PILCs, this article is focused on analyzing scientific publications such as research/review articles and book chapters from the last four decades (from 1980 to 2019) through a bibliometric analysis (BA) to visualize and describe research trends on PILCs. By narrowing the bibliographic search to titles, keywords, and abstracts of publications related to PILCs, using Scopus and Web of Science (WoS) (the two scientific databases), a total of 3425 documents have been retrieved. The bibliometric dataset was analyzed by VantagePoint®. The main research trends identified in the last four decades were the use of PILCs in environmental processes (34.4% of total publications) along with chemical processes (petrochemical reactions 17.5%, SCR NOx 10.8%, and decomposition 8.2%). In environmental processes, PILCs have been used in photo-oxidation (32%), CWPO (21.1%), and heterogeneous catalysis (19.4%). Phenols, dyes, and VOCs have been the main pollutants studied using PILCs as catalysts. Fe, Ti, Zr, Cu, and Co are the most supported active phases in PILCs. Other research trends grouped by characterization techniques, countries, research areas, institutes, scientific journals that have published the most on this topic, number of publications per 5-year period, and most frequently used keywords through the last four decades have been identified. It was determined that the number of publications on PILCs has increased since 1980 and the countries with the highest number of publications are China, Spain, and The United States of America.

Putting glass doors on the display cases of refrigerators is one of the most efficient ways to reduce the energy consumption of supermarkets. However, the glass fogs up when opening the door because of the difference in air temperature inside and outside of the refrigerator, thereby obscuring the view. To defog the glass, anti-sweat heaters (ASHs) are used. In this paper, the power usage of ASHs according to changes in the dew point (DP) inside a supermarket were evaluated for two types of ASH, i.e., the door-frame ASH and the glass ASH. The evaluation was based on measurements of the condensation on the glass doors of vertical display cases, used for the preservation of frozen foodstuffs. A mathematical model of the correlation between the ASH’s power usage and the DP was developed and used for predicting the long-term energy savings. The savings were calculated based on the measured DPs inside the supermarket, which were extrapolated over a longer time period based on their correlation with the outside DPs. Regulating the door-frame ASH according to the DP resulted in an 84.6% reduction in energy consumption and a 90.1% reduction in the case of the glass ASH, compared to the current state. The correlation between the DPs inside and outside the supermarket served as a basis for the proposed implementation of the power usage regulation of the ASH according to the DP.

Applications of polyelectrolytes as pharmaceutical excipients or biologically active agents generated an increased interest in formulations, in which ionic macromolecules share the same milieu with protein drugs or vaccine antigens. Macromolecular interactions, which often take place in such systems, can potentially impact formulation activity and stability. The present article reports that poly[di(carboxylatophenoxy)phosphazene], disodium salt (PCPP), which has been previously shown to be a potent vaccine adjuvant, also displays a strong protein stabilizing effect in aqueous solutions that can be significantly amplified in the presence of nonionic surfactants. The phenomenon is studied in the context of macromolecular interactions in the system and is linked to the formation of PCPP−protein and PCPP−protein−surfactant complexes. [ABSTRACT FROM AUTHOR]

Polyphosphazene polyelectrolytes containing various amounts of hydrophobic fluorinated moieties and ionic carboxylic acid groups were synthesized. Polymer compositions and molecular weights were characterized by NMR and gel permeation chromatography. Interestingly, poly[(carboxylatophenoxy)(trifluoroethoxy)phosphazene] containing 60 mol % fluorinated groups was found to be soluble in aqueous solutions. The behavior of fluorinated polyelectrolytes in reactions of ionic complexation with multivalent and monovalent salts was studied in aqueous solutions and ethanol–water mixtures. Such reactions led to the formation of ionotropic hydrogels under mild conditions and, thus, are of importance to the development of microencapsulation processes and controlled release formulations. All of the synthesized polymers underwent phase separation in the presence of multivalent ionic crosslinkers, such as spermine and calcium chloride. This included a water‐soluble polyelectrolyte containing 40 mol % ionic groups and hydrophobic polymer with only 3 mol % carboxylic acid groups. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 53–58, 2007 [ABSTRACT FROM AUTHOR]

Los impactos que tiene la eliminación de los manglares sobre las comunidades de macroinvertebrados bénticos son inciertos y poco estudiados en Colombia, particularmente en la región Caribe. Este trabajo estudió el efecto de la conversión del manglar a potrero sobre la población del cangrejo azul Cardisoma guanhumi (Decapoda: Gecarcinidae) en el manglar de la bahía El Uno, golfo de Urabá (Colombia). De marzo a abril de 2012, se llevó a cabo un muestreo diario de especímenes en tres coberturas de vegetación diferentes: en el interior del manglar, en el potrero y en el borde (borde antropogénico ocasionado por la deforestación del manglar). Se comparó la distribución, abundancia, peso y tamaño corporal de especímenes de C. guanhumi y la abundancia, diámetro y bioturbación de las madrigueras. Durante Semana Santa se realizaron visitas y entrevistas a los recolectores de cangrejo azul. Se encontró un número de individuos en el interior del manglar (140) mayor que en el potrero (105) y que en el borde (35), e igualmente fue superior el peso corporal y tamaño del cefalotórax en el manglar que en las otras coberturas, las cuales no presentaron diferencias significativas entre sí. En cuanto a las madrigueras no hubo diferencias en su número y sedimentos expulsados (bioturbación) en las distintas coberturas y tampoco hubo una correlación significativa entre el diámetro de la madriguera y la bioturbación. La presión antrópica sobre la población de cangrejos durante el muestreo fue alta, debido a la temporada de caza. En conclusión, se demostró que hay un efecto borde sobre la población de C. guanhumi inducido por la conversión del bosque de manglar a potrero.

Abstract Background We recently described that HIV latent infection can be established in vitro following incubation of resting CD4+ T-cells with chemokines that bind to CCR7. The main aim of this study was to fully define the post-integration blocks to virus replication in this model of CCL19-induced HIV latency. Results High levels of integrated HIV DNA but low production of reverse transcriptase (RT) was found in CCL19-treated CD4+ T-cells infected with either wild type (WT) NL4.3 or single round envelope deleted NL4.3 pseudotyped virus (NL4.3- Δenv). Supernatants from CCL19-treated cells infected with either WT NL4.3 or NL4.3- Δenv did not induce luciferase expression in TZM-bl cells, and there was no expression of intracellular p24. Following infection of CCL19-treated CD4+ T-cells with NL4.3 with enhanced green fluorescent protein (EGFP) inserted into the nef open reading frame (NL4.3- Δnef-EGFP), there was no EGFP expression detected. These data are consistent with non-productive latent infection of CCL19-treated infected CD4+ T-cells. Treatment of cells with phytohemagluttinin (PHA)/IL-2 or CCL19, prior to infection with WT NL4.3, resulted in a mean fold change in unspliced (US) RNA at day 4 compared to day 0 of 21.2 and 1.1 respectively (p = 0.01; n = 5), and the mean expression of multiply spliced (MS) RNA was 56,000, and 5,000 copies/million cells respectively (p = 0.01; n = 5). In CCL19-treated infected CD4+ T-cells, MS-RNA was detected in the nucleus and not in the cytoplasm; in contrast to PHA/IL-2 activated infected cells where MS RNA was detected in both. Virus could be recovered from CCL19-treated infected CD4+ T-cells following mitogen stimulation (with PHA and phorbyl myristate acetate (PMA)) as well as TNFα, IL-7, prostratin and vorinostat. Conclusions In this model of CCL19-induced HIV latency, we demonstrate HIV integration without spontaneous production of infectious virus, detection of MS RNA in the nucleus only, and the induction of virus production with multiple activating stimuli. These data are consistent with ex vivo findings from latently infected CD4+ T-cells from patients on combination antiretroviral therapy, and therefore provide further support of this model as an excellent in vitro model of HIV latency.

Drug synergies impact the efficacy of combination therapies but are difficult to identify. Here Narayan et al. describe the drug atlas, a method to predict effective drug combinations from common exclusive drug effects providing a resource for exploring and understanding effective drug combinations.