Synthesis, biological evaluation, and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis: Part 2. Synthesis of rigid pyrazolones

Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC = 4 μg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity

Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis

As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC = 4 μg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure–activity relationship analysis

Aspecto pragmático del populismo político Albanés en la formación de la agenda de política exterior

The study aims to address the question of the ability to implement democratic principles on a legal basis on the example of the Albanian political space. In a historical retrospective, the author analysed the formation and characteristics of Albania's political institutions, including the challenges of the transition period since 1997. The value orientations of the political space of a functioning democracy at the institutional level are defined. The study noted that Albanian political reality and behaviour are characterised by the prevalence of antagonistic principles, which can lead to the totalisation of society. At the same time, Albania's political space is characterised by the phenomenon of political absenteeism, which allows for the correlation of mass public opinion following the political interests of the ruling elite. The author traced the negative impact of political populism, which is curtailing basic democratic principles. This study is of practical importance, as it can be used during scientific seminars, narrowly focused or multidisciplinary conferences, and in discussions among academics and researchers.El estudio pretende abordar la cuestión de la capacidad de aplicar los principios democráticos sobre una base jurídica tomando como ejemplo el espacio político albanés. En una retrospectiva histórica, el autor analiza la formación y las características de las instituciones políticas albanesas, incluidos los retos del período de transición desde 1997. Se definen las orientaciones de valor del espacio político de una democracia que funciona a nivel institucional. El estudio constata que la realidad y el comportamiento políticos albaneses se caracterizan por la prevalencia de principios antagónicos, que pueden conducir a la totalización de la sociedad. Al mismo tiempo, el espacio político albanés se caracteriza por el fenómeno del absentismo político, que permite la correlación de la opinión pública de masas siguiendo los intereses políticos de la élite gobernante. El autor rastreó el impacto negativo del populismo político, que está cercenando los principios democráticos básicos. Este estudio tiene una importancia práctica, ya que puede utilizarse en seminarios científicos, conferencias de enfoque específico o multidisciplinar, y en debates entre académicos e investigadores

Defining transcriptional signatures of susceptibility for ceftriaxone and tetracycline in Neisseria gonorrhoeae

Resistance to antibiotics is the ability of bacteria to survive in spite of the administration of drugs designated to kill them; and overuse of antibiotics over the past decades has led to a vast increase in resistance. Most infections are treated empirically, such that patients are given a recommended course of antibiotics, however these infections are not frequently tested for their antimicrobial susceptibility profiles (i.e., tested only in the case of treatment failure). This can lead to inappropriate prescription which can increase the selective pressure of antibiotics on other bacterial members of our microbiomes. Susceptibility testing would help determine the antibiotics that are the most effective in helping the prompt treatment of disease-causing organism. In this study we nominated biological signatures to serve as the foundation for developing a point-of-care (POC) diagnostic tool for antimicrobial susceptibility testing. RNA transcriptional signatures of Neisseria gonorrhoeae were generated upon drug exposure, as RNA abundance change can define susceptibility; susceptible bacteria are expected to express a stress response after drug exposure, which is absent in resistant bacteria. These profiles were then analyzed to identify Treatment-Susceptibility (TS) patterns; those transcripts differentially expressed in susceptible cells across treatment, and differentially expressed in the treatment condition. The transcripts exhibiting distinct TS pattern were investigated for each drug contrast and at two specific time points i.e., 120 minutes and 240 minutes. We identify 61 transcripts that show the TS pattern for ceftriaxone at 120 minutes and 7 at 240; and 18 transcripts that show the TS pattern for tetracycline at 120 minutes and 128 at 240. The results indicate that RNA abundance changes can reliably signify bacterial susceptibility, as susceptible isolates demonstrate a clear transcriptional response to drug exposure. This study also demonstrated that to acquire meaningful results it is crucial to test transcripts at specific timepoints, as they capture the dynamic transcriptional response of bacteria to drug exposure. By nominating these biological signatures, this study lays the groundwork for developing a rapid, RNA- based diagnostic tool. Such a tool could enhance susceptibility testing, reduce inappropriate antibiotic use, and support more targeted treatment strategies. Overall, these findings depicted the most useful transcriptional signatures, which could serve as a key component in future point-of-care (POC) devices for antimicrobial susceptibility testing

TRPA1 mediates aromatase inhibitor-evoked pain by the aromatase substrate androstenedione

Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS

European Union (Aims and Values)

European Union (Aims and Values) combines theoretical knowledge, practical examples, interactive learning, and assessments to give learners a deep understanding of EU governance, environmental policy, and participatory democracy. The module is built on a Literature Review conducted through Web of Science, Scopus, and Science Direct, using queries related to "European Union- Member" and "Participation," as well as "European Union" and "Aims/Values." This search was aimed at exploring the EU's approach to engaging stakeholders in policymaking, emphasizing the importance of such participation for democracy and sustainability. We selected articles and review articles in English, with no time restriction, to ensure a comprehensive and relevant content base for the course

The role of extracellular polymers on Staphylococcus epidermidis biofilm biomass and metabolic activity

Staphylococcus epidermidis is now well established as being a major nosocomial pathogen, associated with indwelling medical devices. Its major virulence factor is related with the ability to adhere to indwelling medical devices, with consequent biofilm formation. The present study aimed to evaluate the role of polysaccharides and proteins on biofilm biomass and metabolic activity of five S. epidermidis clinical isolates. For this purpose, S. epidermis biofilms, formed on acrylic coupons, were characterized in terms of total biofilm biomass, determined through crystal violet assay, cell concentration, established by colony forming units (CFU) enumeration, and biofilm matrix composition, which was assessed for polysaccharides and proteins content. Biofilm metabolic activity was evaluated by two distinct methods: glucose uptake and XTT reduction assays. According to the results, S. epidermidis strains revealed different abilities for biofilm formation. In fact, some strains were able to form thicker biofilms than others and this is important because biofilm formation is considered one of the major virulence factors of S. epidermidis species. S. epidermidis 1457 was the strain that produced the larger amount of biofilm and strain LE7 was the lowest biofilm producer, and these were also the highest and the lowest polysaccharides producers, respectively. This suggests a certain degree of correlation between exopolysaccharides production and total amount of biomass formed. Besides, comparing the results obtained, in terms of exopolysaccharides production and biofilm cellular activity, it seems clear that a strong production of exopolysaccharides can lead to a decrease in the metabolic activity of cells, which was the case of S. epidermidis 1457. The protein concentration also varied among strains, with the biofilm matrix of S. epidermidis 9142 presenting a higher concentration of proteins comparing to the remaining strains. This fact indicates the different levels of importance that matrix proteins can have on biofilm composition among strains albeit overall, it is suggested that extracellular protein production it is not a determinant factor for biofilm total biomass, despite its qualitative value. In conclusion, this work provided a reliable approach for a better understanding of S. epidermidis biofilms composition and metabolic activity