Reduction-responsive polymers for drug delivery in cancer therapy—Is there anything new to discover?

© 2020 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC. Among various types of stimuli-responsive drug delivery systems, reduction-responsive polymers have attracted great interest. In general, these systems have high stability in systemic circulation, however, they can respond quickly to differences in the concentrations of reducing species in specific physiological sites associated with a pathology. This is a particularly relevant strategy to target diseases in which hypoxic regions are present, as polymers which are sensitive to in-situ expressed antioxidant species can, through a local response, release a therapeutic at high concentration in the targeted site, and thus, improve the selectivity and efficacy of the treatment. At the same time, such reduction-responsive materials can also decrease the toxicity and side effects of certain drugs. To date, polymers containing disulfide linkages are the most investigated of the class of reduction-responsive nanocarriers, however, other groups such as selenide and diselenide have also been used for the same purpose. In this review article, we discussed the rationale behind the development of reduction-responsive polymers as drug delivery systems and highlight examples of recent progress. We include the most popular design methods to generate reduction-responsive polymeric carriers and their applications in cancer therapy, and question what areas may still need to be explored in a field with already a very large number of research articles. Finally, we consider the main challenges associated with the clinical translation of these nanocarriers and the future perspectives in this area. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies

Interpretation of gravity data to delineate structural features connected to low-temperature geothermal resources at Northeastern Portugal

A great number of low-temperature geothermal fields occur in Northern-Portugal related to fractured rocks. The most important superficial manifestations of these hydrothermal systems appear in pull-apart tectonic basins and are strongly conditioned by the orientation of the main fault systems in the region. This work presents the interpretation of gravity gradient maps and 3D inversion model produced from a regional gravity survey. The horizontal gradients reveal a complex fault system. The obtained 3D model of density contrast puts into evidence the main fault zone in the region and the depth distribution of the granitic bodies. Their relationship with the hydrothermal systems supports the conceptual models elaborated from hydrochemical and isotopic water analyses. This work emphasizes the importance of the role of the gravity method and analysis to better understand the connection between hydrothermal systems and the fractured rock pattern and surrounding geology. (c) 2013 Elsevier B.V. All rights reserved

Passerini chemistries for synthesis of polymer pro-drug and polymersome drug delivery nanoparticles

New materials chemistries are urgently needed to overcome the limitations of existing biomedical materials in terms of preparation, functionality and versatility, and also in regards to their compatibility with biological environments. Here, we show that Passerini reactions are especially suited for the preparation of drug delivery materials, as with relatively few steps, polymers can be synthesized with functionality installed enabling drug conjugation and encapsulation, self-assembly into micellar or vesicular architectures, and with facile attachment triggerable chemistries. The polymers can be made with a variety of building blocks and assemble into nanoparticles, which are rapidly internalized in triple negative breast cancer (TNBC) cells. In addition, the polymers transport drug molecules efficiently through 3D cell cultures, and when designed with chemistries allowing pH-mediated release, exhibit greater efficacy against TNBC cells compared to the parent drug

Providing office workers with height-adjustable workstation to reduce and interrupt workplace sitting time: protocol for the Stand Up for Healthy Aging (SUFHA) cluster randomized controlled trial

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Sedentary behavior (SB) has been linked to several negative health outcomes. Therefore, reducing SB or breaking up prolonged periods of SB improves functional fitness, food consumption, job satisfaction, and productivity. Reducing SB can be achieved by introducing a health-enhancing contextual modification promoted by a sit-stand desk in the workplace. The primary goal will be to test the effectiveness of this intervention in reducing and breaking up SB, while improving health outcomes in office-based workers during a 6-month intervention. Methods: A two-arm (1:1), superiority parallel-group cluster RCT will be conducted to evaluate the effectiveness of this intervention in a sample of office-based workers from a university in Portugal. The intervention will consist of a psychoeducation session, motivational prompts, and contextual modification promoted by a sit-stand desk in the workplace for 6 months. The control group will work as usual in their workplace, with no contextual change or prompts during the 6-month intervention. Three assessment points will be conducted in both groups, pre-intervention (baseline), post-intervention, and a 3-month follow-up. The primary outcomes include sedentary and physical activity-related variables, which will be objectively assessed with 24 h monitoring using the ActivPAL for 7 days. The secondary outcomes include (a) biometric indices as body composition, body mass index, waist circumference, and postural inequalities; and (b) psychosocial variables such as overall and work-related fatigue, overall discomfort, life/work satisfaction, quality of life, and eating behavior. Both the primary and secondary outcomes will be assessed at each assessment point. Discussion: This study will lean on the use of a sit-stand workstation for 6 months, prompted by an initial psychoeducational session and ongoing motivational prompts. We will aim to contribute to this topic by providing robust data on alternating sitting and standing postures in the workplace. Trial registration: The trial was prospectively registered, and the details are at: https://doi.org/10.17605/OSF.IO/JHGPW ; Registered 15 November 2022. OSF Preregistration.This study was funded by the ILIND “Fazer+” scientific program (Reference: FAZER+/ILIND/CIDEFES/1/2022).info:eu-repo/semantics/publishedVersio

Tlx3 exerts direct control in specifying excitatory over inhibitory neurons in the dorsal spinal cord

© 2021 Monteiro, Miranda, Samina, Dias, Raposo, Oliveira, Reguenga, Castro and Lima. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The spinal cord dorsal horn is a major station for integration and relay of somatosensory information and comprises both excitatory and inhibitory neuronal populations. The homeobox gene Tlx3 acts as a selector gene to control the development of late-born excitatory (dILB) neurons by specifying glutamatergic transmitter fate in dorsal spinal cord. However, since Tlx3 direct transcriptional targets remain largely unknown, it remains to be uncovered how Tlx3 functions to promote excitatory cell fate. Here we combined a genomics approach based on chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) and expression profiling, with validation experiments in Tlx3 null embryos, to characterize the transcriptional program of Tlx3 in mouse embryonic dorsal spinal cord. We found most dILB neuron specific genes previously identified to be directly activated by Tlx3. Surprisingly, we found Tlx3 also directly represses many genes associated with the alternative inhibitory dILA neuronal fate. In both cases, direct targets include transcription factors and terminal differentiation genes, showing that Tlx3 directly controls cell identity at distinct levels. Our findings provide a molecular frame for the master regulatory role of Tlx3 in developing glutamatergic dILB neurons. In addition, they suggest a novel function for Tlx3 as direct repressor of GABAergic dILA identity, pointing to how generation of the two alternative cell fates being tightly coupled.This work is a result of the project Norte-01-0145-FEDER-000008 – Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work was also supported by FCT – Fundação para a Ciência e Tecnologia (Grants PTDC/SAU-OBD/099886/2008 to DL and PTDC/NEU-NMC/0315/2012 to DC) and Universidade do Porto/Banco Santander Totta (Projetos Pluridisciplinares to FM). We acknowledge the support of POCI-01-0145-FEDER-022122, granted to i3S Scientific Platform Advanced Light Microscopy, member of the national infrastructure PPBI-Portuguese Platform of BioImaging.info:eu-repo/semantics/publishedVersio

Synthesis of Passerini-3CR Polymers and Assembly into Cytocompatible Polymersomes

© 2020 The Authors. Published by Wiley-VCH GmbH The versatility of the Passerini three component reaction (Passerini-3CR) is herein exploited for the synthesis of an amphiphilic diblock copolymer, which self-assembles into polymersomes. Carboxy-functionalized poly(ethylene glycol) methyl ether is reacted with AB-type bifunctional monomers and tert-butyl isocyanide in a single process via Passerini-3CR. The resultant diblock copolymer (P1) is obtained in good yield and molar mass dispersity and is well tolerated in model cell lines. The Passerini-3CR versatility and reproducibility are shown by the synthesis of P2, P3, and P4 copolymers. The ability of the Passerini P1 polymersomes to incorporate hydrophilic molecules is verified by loading doxorubicin hydrochloride in P1DOX polymersomes. The flexibility of the synthesis is further demonstrated by simple post-functionalization with a dye, Cyanine-5 (Cy5). The obtained P1-Cy5 polymersomes rapidly internalize in 2D cell monolayers and penetrate deep into 3D spheroids of MDA-MB-231 triple-negative breast cancer cells. P1-Cy5 polymersomes injected systemically in healthy mice are well tolerated and no visible adverse effects are seen under the conditions tested. These data demonstrate that new, biodegradable, biocompatible polymersomes having properties suitable for future use in drug delivery can be easily synthesized by the Passerini-3CR

Passerini chemistries for synthesis of polymer pro-drug and polymersome drug delivery nanoparticles

New materials chemistries are urgently needed to overcome the limitations of existing biomedical materials in terms of preparation, functionality and versatility, and also in regards to their compatibility with biological environments. Here, we show that Passerini reactions are especially suited for the preparation of drug delivery materials, as with relatively few steps, polymers can be synthesized with functionality installed enabling drug conjugation and encapsulation, self-assembly into micellar or vesicular architectures, and with facile attachment triggerable chemistries. The polymers can be made with a variety of building blocks and assemble into nanoparticles, which are rapidly internalized in triple negative breast cancer (TNBC) cells. In addition, the polymers transport drug molecules efficiently through 3D cell cultures, and when designed with chemistries allowing pH-mediated release, exhibit greater efficacy against TNBC cells compared to the parent drug

First records of Ingoldian fungi from the Brazilian Amazon

Ingoldian fungi play an important ecological role by active participation in the decomposition of submerged leaves in aquatic ecosystems. These fungi produce conidia that are filiform, tetraradiate, multiradiate, scolecoid or sigmoid, which aid in the adaptation and dispersal in freshwater habitats. Despite their important ecological role in freshwater there have been no taxonomic and distributional studies of these fungi in the Brazilian Amazon. The aim of this study was to report new records of Ingoldian fungi to Americas, Brazil and Brazilian Amazon region. The fungal specimens were obtained from natural foam, found on the surface of streams in the “Reserva Ducke” (municipality of Manaus) and the “Balneário Marupiara” (municipality of Presidente Figueiredo) in Amazonas state, Brazil. The foam samples were transferred to slides and completely evaporated at room temperature. Lactic acid was added to the slides and covered using a glass cover slip and sealed with nail polish. Seventeen taxa were recorded. All identified taxa are new records: one new to the Americas (Tricladium curvisporum Descals), three new to Brazil (Condylospora flexuosa Nawawi and Kuthub., C. spumigena Nawawi and Dwayaangam cornuta Descals), and 13 new to the Brazilian Amazon region. Our study provides baseline data on the species composition of Ingoldian fungi from the Brazilian Amazon region, thereby enhancing the knowledge of aquatic mycology in this biodiversity hotspot. Descriptions, illustrations, geographical distribution patterns and comments are presented for all observed species. © 2015, Botanical Society of Sao Paulo

Fluorophore Selection and Incorporation Contribute to Permeation and Distribution Behaviors of Hyperbranched Polymers in Multi-Cellular Tumor Spheroids and Xenograft Tumor Models

Improving our understanding of how design choices in materials synthesis impact biological outcomes is of critical importance in the development of nanomedicines. Here, we show that fluorophore labeling of polymer nanomedicine candidates significantly alters their transport and cell association in multi-cellular tumor spheroids and their penetration in breast cancer xenografts, dependent on the type of the fluorophore and their positioning within the macromolecular structure. These data show the critical importance of the biomaterials structure and architecture in their tissue distribution and intracellular trafficking, which in turn govern their potential therapeutic efficacy. The broader implication of these findings suggests that when developing materials for medical applications, great care should be taken early on in the design process as relatively simple choices may have downstream impacts that could potentially skew preclinical biology data

Low-temperature dielectric measurements of confined water in porous granites

Three different granitic rocks extracted from Évora (in the south of Portugal) where used to perform dielectric measurements in the frequency range from 100 Hz to 1 MHz and temperatures 100 − 350 K. Thin cylindrical samples were prepared and circular electrodes were established using silver conductive paint. A clear anomaly appears, for T ⇠ 200 − 220 K, in the dielectric measurements of the samples studied. This anomaly occurs in different materials and coincides with a phase transition of supercooled water. Tightly bounded water confined in the pores of the rock do not crystallize at 273 K, but form a metastable liquid down to 200−220 K increasing water polarization. Below this temperature water molecules solidify and polarizability decreases. The rock presenting the most sizeable anomaly has a very low specific surface area, ⇠ 0.09 m2