Activation of benzoate model prodrugs by mycobacteria. Comparison with mammalian plasma and liver hydrolysis.

Due to difficulties in drug penetration in M. tuberculosis, a prodrug approach based on mycobacterial activation appears as a promising strategy to increase the delivery of antitubercular drugs to the target microorganisms. Esters have been successful used by us and others to deliver drugs to mycobacteria, however because very little is known about the metabolic hydrolysis of esters by mycobacteria in connection with prodrug activation, we decided to study the process further. For that we selected a series of 13 benzoates with different chain lengths and ramifications in the alkoxy side as model prodrugs and examined their hydrolysis by a mycobacterial homogenate, comparing the results with those obtained parallelly in human plasma and in total rat liver homogenate. In all biological media, the benzoates with a linear alkyl group showed a parabolic dependence between log(k) and logP (or the number of carbons of the linear alkyl chain) that reached a maximal value for the n-butyl chain. Considering linear correlations for the total number of compounds between log(k) and chosen descriptors, for mycobacterial esterases, pKa of the leaving alcohol (pKa <sub>LG</sub> ) seem to be the most important descriptor. Plasma esterases seem to be quite sensitive to the Taft polarity parameter σ* and also to pKa <sub>LG</sub> and less sensitive to steric effects. Liver esterases seem to be more sensitive to the Taft steric descriptor E <sub>S</sub> <sup>c</sup> . Lipophilicity correlates weakly with log(k) in all the 3 media, however, is more important when one looks for mycobacterial activation selectivity in relation to plasma metabolism or in relation to liver homogenate metabolism. The importance of lipophilicity increases further when biparametric expressions are considered. We showed that it is easy to activate a wide variety of benzoate esters using a mycobacterial homogenate. The data also suggest that with careful design is possible to obtain tuberculostatic prodrug esters sensitive to mycobacterial hydrolases while reasonably resistant to plasma and liver hydrolysis. One important observation is that mycobacterial hydrolysis is less affected by bulky substituents than liver homogenate or plasma hydrolysis. tert-Butyl is probably the substituent in the alkoxy side that seems more adequate to resist simultaneously plasma and liver metabolism, while allowing activation by mycobacterial esterases. Hexyl is also a good option for the medicinal chemist if a linear alkoxy chain is needed

Influence of Prolonged Serotonin and Ergovaline Pre-Exposure on Vasoconstriction Ex Vivo

Ergot alkaloid mycotoxins interfere in many functions associated with serotonergic neurotransmitters. Therefore, the objective was to evaluate whether the association of serotonin (5-hydroxytryptamine, 5-HT) and ergot alkaloids during a 24 h pre-incubation could affect the vascular contractile response to ergot alkaloids. To evaluate the effects of 24 h exposure to 5-HT and ergot alkaloids (ergovaline, ERV), two assays were conducted. The first assay determined the half-maximal inhibitory concentration (IC50)following the 24 h pre-exposure period, while the second assay evaluated the effect of IC50 concentrations of 5-HT and ERV either individually or in combination. There was an interaction between previous exposure to 5-HT and ERV. Previous exposure to 5-HT at the IC50 concentration of 7.57 × 10−7 M reduced the contractile response by more than 50% of control, while the exposure to ERV at IC50 dose of 1.57 × 10−10 M tended to decrease (p = 0.081) vessel contractility with a response higher than 50% of control. The 24 h previous exposure to both 5-HT and ERV did not potentiate the inhibitory response of blood vessels in comparison with incubation with each compound alone. These results suggest receptor competition between 5-HT and ERV. More studies are necessary to determine the potential of 5-HT to treat toxicosis caused by ergot alkaloids

Assembly in G1 phase and long-term stability are unique intrinsic features of CENP-A nucleosomes

Centromeres are the site of kinetochore formation during mitosis. Centromere protein A (CENP-A), the centromere-specific histone H3 variant, is essential for the epigenetic maintenance of centromere position. Previously we showed that newly synthesized CENP-A is targeted to centromeres exclusively during early G1 phase and is subsequently maintained across mitotic divisions. Using SNAP-based fluorescent pulse labeling, we now demonstrate that cell cycle-restricted chromatin assembly at centromeres is unique to CENP-A nucleosomes and does not involve assembly of other H3 variants. Strikingly, stable retention is restricted to the CENP-A/H4 core of the nucleosome, which we find to outlast general chromatin across several cell divisions. We further show that cell cycle timing of CENP-A assembly is independent of centromeric DNA sequences and instead is mediated by the CENP-A targeting domain. Unexpectedly, this domain also induces stable transmission of centromeric nucleosomes, independent of the CENP-A deposition factor HJURP. This demonstrates that intrinsic properties of the CENP-A protein direct its cell cycle-restricted assembly and induces quantitative mitotic transmission of the CENP-A/H4 nucleosome core, ensuring long-term stability and epigenetic maintenance of centromere position.FCT fellpwships: (SFRH/BD/74284/2010, SFRH/BPD/69115/2010), National Institutes of Health grant: (GM082989), Burroughs Wellcome Fund (Career Award in the Biomedical Sciences), Rita Allen Foundation Scholar Award, Instituto Gulbenkian de Ciência, European Commission FP7 Program, EMBO

A Fabry-Perot interferometer with quantum mirrors: nonlinear light transport and rectification

Optical transport represents a natural route towards fast communications, and it is currently used in large scale data transfer. The progressive miniaturization of devices for information processing calls for the microscopic tailoring of light transport and confinement at length scales appropriate for the upcoming technologies. With this goal in mind, we present a theoretical analysis of a one-dimensional Fabry-Perot interferometer built with two highly saturable nonlinear mirrors: a pair of two-level systems. Our approach captures non-linear and non-reciprocal effects of light transport that were not reported previously. Remarkably, we show that such an elementary device can operate as a microscopic integrated optical rectifier

Optimal irreversible stimulated emission

We studied the dynamics of an initially inverted atom in a semi-infinite waveguide, in the presence of a single propagating photon. We show that atomic relaxation is enhanced by a factor of 2, leading to maximal bunching in the output field. This optimal irreversible stimulated emission is a novel phenomenon that can be observed with state-of-the-art solid-state atoms and waveguides. When the atom interacts with two one-dimensional electromagnetic environments, the preferential emission in the stimulated field can be exploited to efficiently amplify a classical or a quantum state.Comment: 9 pages, 6 figure

Environmental Regeneration Integrating Soft Mobility and Green Street Networks: A Case Study in the Metropolitan Periphery of Naples

Public space and street networks form a significant and central determinant of urban quality. The advent of the COVID-19 pandemic has focused their crucial importance in the reorganisation of places that are “safe” because they allow movement through cities with minimal risk of contagion. While addressing the need for social distancing, open-air exercise, and mobility without the use of public transport, these measures resulted in other environmental and social benefits. Living with the coronavirus pandemic has produced a series of adaptative actions, such as barring or limiting automobile traffic, thereby expanding street space for pedestrians and bicyclists, whose impact is, as yet, difficult to fathom because of their contingent, temporary nature. In this context, this case study proposes a sustainable bicycle network to inform the future, permanent street redesign. Based on topographic, morphologic, and climatic data, it evaluates a series of contiguous road sections, defining redesign capacities and critical conditions to implement sustainable interventions to manage urban runoff, mitigate of extreme heat events, expand pedestrian paths and provide a bicycle network. This holistic approach to sustainable urban design evaluation, supported by reproducible data and parameters, serves as a replicable model for the sustainable redesign of roads in other urban settings. The extent, integration, and complexity of the study engaged an interdisciplinary framework, facilitating detailed planning and design and quantified assessments of the environmental outcomes

Universal optimal broadband photon cloning and entanglement creation in one dimensional atoms

We study an initially inverted three-level atom in the lambda configuration embedded in a waveguide, interacting with a propagating single-photon pulse. Depending on the temporal shape of the pulse, the system behaves either as an optimal universal cloning machine, or as a highly efficient deterministic source of maximally entangled photon pairs. This quantum transistor operates over a wide range of frequencies, and can be implemented with today's solid-state technologies.Comment: 5 pages, 3 figure

Morphological and biochemical changes in trisomy 21

Introdução: A Trissomia 21 (T21) é a aneuploidia mais comum, apresentando uma prevalência de 1/670 nascimentos. É a principal causa de défice intelectual moderado a grave, e está associada a diversas anomalias congénitas, sendo as malformações cardiovasculares as mais frequentes. O objetivo deste trabalho é caracterizar as alterações morfológicas e bioquímicas nos casos de T21. Material e Métodos: Estudo prospetivo, realizado no nosso Hospital entre 1998 e 2008, de avaliação dos casos com rastreio bioquímico considerado positivo para T21. Foram também analisados os resultados dos exames invasivos realizados no mesmo período e revistos os processos com diagnóstico de T21 neste exame, assim como os processos das mães cujos recém-nascidos foram codificados com diagnóstico de T21 na alta. Resultados: Neste período foram efetuados 12163 rastreios. Foram identificados 18 casos de T21. Houve 2 resultados falsos-negativos, representando uma taxa de deteção do rastreio de 88,9%. A mediana das MoM's dos marcadores bioquímicos nas grávidas com fetos afetados foi: 0,735 de AFP, 0,685 de µE3 e 2,54 de βHCG. Quinze dos 18 casais optaram por interromper a gravidez. Nasceram 3 recém-nascidos com T21. As anomalias presentes nos fetos afetados foram essencialmente alterações do hábito externo, nomeadamente a existência de pregas palmares transversais em uma ou ambas as mãos e alterações craniofaciais. Quanto às alterações do hábito interno as mais comuns foram as malformações cardiovasculares, nomeadamente a comunicação interventricular (CIV). Discussão: Neste estudo a taxa de deteção do rastreio foi elevada. A maioria dos casais optou por interromper a gravidez. A maioria dos fetos e recém-nascidos afetados apresentou alterações morfológicas subtis, difíceis de detetar ecograficamente, salientando a importância do rastreio bioquímico.info:eu-repo/semantics/publishedVersio

Validation study of the Italian brief version of the multidimensional jealousy scale: Psychometric properties, measurement invariance across gender, and convergent validity

INTRODUCTION: The multidimensional jealousy scale (MJS) is among the most internationally used instruments for the assessment of jealousy in its three dimensions: cognitive, emotional, and behavioral. This study aimed to replicate the Italian validation process of the shortened MJS in order to confirm its psychometric properties and measurement invariance across gender. MATERIALS AND METHODS: Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted in a large sample of adults (n = 2,928). To reliably estimate mean differences across gender, the measurement invariance of the scale was first established by means of CFA. Convergent validity was than tested by administrating the tool to a convenient sample (n = 304). RESULTS: A 15-item version of the Italian MJS was retained in its three-factor structure. The tool showed good fit with both the CFA (χ(2) = 211.827, CFI = 0.969, TLI = 0.959, RMSEA = 0.047, RMSEA 90% CI = 0.039–0.055) and the results confirmed the strong measurement invariance of the MJS across gender. The internal consistency measures were found to be fully satisfactory. Predictive associations with constructs such as avoidance and anxiety referred to attachment in relationships (ECR-R), obsessive jealousy, depressive jealousy, jealousy associated with separation anxiety, paranoid jealousy (QUEGE), and basic self-esteem (BSE) were confirmed. DISCUSSION: The MJS is particularly apt to collect information quickly and efficiently about jealousy in a current relationship. The multidimensional and brief structure makes it particularly suitable for preliminary screening, couple therapy assessment, and research purposes