We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: cis-dichloro(diamine)-trans-3-(triethoxysilyl)propylcarbamateplatinum(IV) (Pt(IV)-biSi-1) and ...cis-dichloro(diisopropylamine)-trans-3-(triethoxysilyl) propyl carbamateplatinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt(IV)-biSi-2 outperformed cisplatin in reducing tumor growth at lower concentrations, with reduced side effects. Mechanistically, Pt(IV)-biSi-2 induced permanent DNA damage independent of p53 levels. DNA damage such as double-strand breaks marked by histone gH2Ax was permanent after treatment with Pt(IV)-biSi-2, in contrast to cisplatin's transient effects. Pt(IV)-biSi-2's faster reduction to Pt(II) species upon exposure to biological reductants supports its superior biological response. These findings unveil a novel strategy for designing Pt(IV) anticancer prodrugs with enhanced activity and specificity, offering therapeutic opportunities beyond conventional Pt drugs.
Perylenediimide (PDI) dyes dispersed in polymer films have demonstrated great success as active materials in thin-film organic lasers (TFOLs). The type of matrix used to host the dye and the dye ...doping rate are both crucial parameters to optimize laser performance. This work reports the study of two soluble PDIs, the comercial derivative perylene orange (PDI-O) emitting at around 580 nm, and a new dye (b-PDI-A) with substituents at the 1,7 bay positions of the PDI core emitting at around 620 nm, dispersed at different doping levels (up to 8 and 50 wt %, for PDI-O and b-PDI-A, respectively) in two widely used polymers for optoelectronics, polystyrene (PS) and poly(methyl methacrylate) (PMMA). The main goal is to determine which of these two polymers, and at which dye concentration, provides the best results for their use in TFOLs. The assessment of the active materials has been carried out through the analysis of their absorption, photoluminescence, and amplified spontaneous emission (ASE) properties. Their capability to form high-quality optical waveguides has also been studied by determining gain coefficients and waveguide losses. Results have shown that for both types of PDI derivatives PS is better than PMMA at any concentration, which means larger photoluminescence efficiency, lower ASE thresholds, longer ASE operational lifetimes, larger gain, and lower propagation waveguide losses. In addition, the onset concentration at which dye aggregation becomes significant as to negatively affect the optical properties is lower in PMMA than in PS; thus, the larger the blending ratio, the larger the superiority of PS with respect to PMMA is.
Modern machine learning algorithms excel in a great variety of tasks, but at the same time, it is also known that those complex models need to deal with uncertainty from different sources. ...Consequently, understanding if the model is indeed making accurate predictions or simply guessing at random is not trivial, and measuring the confidence bounds becomes very important. Bayesian machine learning seems to provide the solution, however, many of the state-of-the-art Bayesian algorithms use rigid parametric representations of the uncertainty where the learning process depends on the gradient of a predefined cost function. In this article, a new gradient-free training algorithm based on Approximate Bayesian Computation by Subset Simulation is proposed, where the likelihood function and the weights are defined by non-parametric formulations, resulting in a flexible and fairer representation of the uncertainty. The experiments, specially the engineering case study on composite materials subject to fatigue damage, show the ability of the proposed algorithm to consistently reach accurate predictions while avoiding gradient related instabilities, and most importantly, it provides a realistic and coherent quantification of the uncertainty represented by confidence bounds. All this may lead to a reduction of safety factors in engineering problems, and in general, allows us to make well-informed decisions in situations with a high degree of uncertainty and risk. A comparison with the state-of-the-art Bayesian Neural Networks is also carried out.
•Neural networks trained with approximate Bayesian computation.•Accurate and flexible representation of the uncertainty in the observed data.•Stability of predictions thanks to the gradient-free nature of the algorithm.•Non-parametric weights and likelihood function provide adaptability to data.•Appropriate when decisions are dependent on the level of uncertainty.
Mesoporous silica nanomaterials have emerged as promising vehicles in controlled drug delivery systems due to their ability to selectively transport, protect, and release pharmaceuticals in a ...controlled and sustained manner. One drawback of these drug delivery systems is their preparation procedure that usually requires several steps including the removal of the structure-directing agent (surfactant) and the later loading of the drug into the porous structure. Herein, we describe the preparation of mesoporous silica nanoparticles, as drug delivery systems from structure-directing agents based on the kidney-protector drug cilastatin in a simple, fast, and one-step process. The concept of drug-structure-directing agent (DSDA) allows the use of lipidic derivatives of cilastatin to direct the successful formation of mesoporous silica nanoparticles (MSNs). The inherent pharmacological activity of the surfactant DSDA cilastatin-based template permits that the MSNs can be directly employed as drug delivery nanocarriers, without the need of extra steps. MSNs thus synthesized have shown good sphericity and remarkable textural properties. The size of the nanoparticles can be adjusted by simply selecting the stirring speed, time, and aging temperature during the synthesis procedure. Moreover, the release experiments performed on these materials afforded a slow and sustained drug release over several days, which illustrates the MSNs potential utility as drug delivery system for the cilastatin cargo kidney protector. While most nanotechnology strategies focused on combating the different illnesses this methodology emphasizes on reducing the kidney toxicity associated to cancer chemotherapy.
El Índice (1773) de la biblioteca del Colegio de Santa Catalina de Córdoba incluye 126 registros de libros escritos en griego comprendidos entre los siglos XVI y XVIII, de los que se analizan las ...materias, sus poseedores y los indicios de lectura que contienen.
Dental caries is the major biofilm-mediated oral disease in the world. The main treatment to restore caries lesions consists of the use of adhesive resin composites due to their good properties. ...However, the progressive degradation of the adhesive in the medium term makes possible the proliferation of cariogenic bacteria allowing secondary caries to emerge. In this study, a dental adhesive incorporating a drug delivery system based on L-arginine-containing mesoporous silica nanoparticles (MSNs) was used to release this essential amino acid as a source of basicity to neutralize the harmful acidic conditions that mediate the development of dental secondary caries. The in vitro and bacterial culture experiments proved that L-arginine was released in a sustained way from MSNs and diffused out from the dental adhesive, effectively contributing to the reduction of the bacterial strains Streptococcus mutans and Lactobacillus casei. Furthermore, the mechanical and bonding properties of the dental adhesive did not change significantly after the incorporation of L-arginine-containing MSNs. These results are yielding glimmers of promise for the cost-effective prevention of secondary caries.
Summary
Higher dietary intakes of flavonoids may have a beneficial role in cardiovascular disease prevention. Additionally, supplementation of branched‐chain amino acids (BCAAs) in vegan diets can ...reduce risks associated to their deficiency, particularly in older adults, which can cause loss of skeletal muscle strength and mass. Most plant‐derived foods contain only small amounts of BCAAs, and those plants with high levels of flavonoids are not eaten broadly. Here we describe the generation of metabolically engineered cisgenic tomatoes enriched in both flavonoids and BCAAs. In this approach, coding and regulatory DNA elements, all derived from the tomato genome, were combined to obtain a herbicide‐resistant version of an acetolactate synthase (mSlALS) gene expressed broadly and a MYB12‐like transcription factor (SlMYB12) expressed in a fruit‐specific manner. The mSlALS played a dual role, as a selectable marker as well as being key enzyme in BCAA enrichment. The resulting cisgenic tomatoes were highly enriched in Leucine (21‐fold compared to wild‐type levels), Valine (ninefold) and Isoleucine (threefold) and concomitantly biofortified in several antioxidant flavonoids including kaempferol (64‐fold) and quercetin (45‐fold). Comprehensive metabolomic and transcriptomic analysis of the biofortified cisgenic tomatoes revealed marked differences to wild type and could serve to evaluate the safety of these biofortified fruits for human consumption.
Axon pathfinding is a key step in neural circuits formation. However, the transcriptional mechanisms regulating its progression remain poorly understood. The binary decision of crossing or avoiding ...the midline taken by some neuronal axons during development represents a robust model to investigate the mechanisms that control the selection of axonal trajectories. Here, to identify novel regulators of axon guidance, this work compares the transcriptome and chromatin occupancy profiles of two neuronal subpopulations, ipsilateral (iRGC) and contralateral retinal ganglion cells (cRGC), with similar functions but divergent axon trajectories. These analyses retrieved a number of genes encoding for proteins not previously implicated in axon pathfinding. In vivo functional experiments confirm the implication of some of these candidates in axonal navigation. Among the candidate genes, γ‐synuclein is identified as essential for inducing midline crossing. Footprint and luciferase assays demonstrate that this small‐sized protein is regulated by the transcription factor (TF) Pou4f1 in cRGCs. It is also shown that Lhx2/9 are specifically expressed in iRGCs and control a program that partially overlaps with that regulated by Zic2, previously described as essential for iRGC specification. Overall, the analyses identify dozens of new molecules potentially involved in axon guidance and reveal the regulatory logic behind the selection of axonal trajectories.
The results presented here provide genomic screens for regarding genes and regulatory regions involved in axonal trajectory selection and offer new biological insight that may contribute to future experiments addressing how neural circuits may be rewired after damage or be useful to improve the generation of artificial neural circuits growing in brain organoids.
In recent years, there has been growing concern in Europe about the lack of an established comparable measure of job quality to complement the widely accepted quantitative indicators in the ...formulation and evaluation of European employment policies. The aim of this paper is to offer a guided tour around the different views and existing proposals of job quality indicators, mainly from a European perspective. First, we discuss the methodological decisions that have to be made in the process of designing an indicator of job quality, from both a theoretical and methodological/technical perspective. Second, these arguments are used to discuss critically the different empirical approaches to the measurement of job quality proposed in the literature. We finish by presenting some recommendations for the construction of a job quality index for policy purposes.
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