Antibacterial activity of 1-[(2,4-dichlorophenethyl)amino]-3-phenoxypropan-2-ol against antibiotic-resistant strains of diverse bacterial pathogens, biofilms and in pre-clinical infection models

We recently described the novel anti-persister compound 1-[(2,4-dichlorophenethyl)amino]-3-phenoxypropan-2-ol (SPI009), capable of directly killing persister cells of the Gram-negative pathogen Pseudomonas aeruginosa. This compound also shows antibacterial effects against non-persister cells, suggesting that SPI009 could be used as an adjuvant for antibacterial combination therapy. Here, we demonstrate the broad-spectrum activity of SPI009, combined with different classes of antibiotics, against the clinically relevant ESKAPE pathogens Enterobacter aerogenes, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa, Enterococcus faecium and Burkholderia cenocepacia and Escherichia coli. Importantly, SPI009 re-enabled killing of antibiotic-resistant strains and effectively lowered the required antibiotic concentrations. The clinical potential was further confirmed in biofilm models of P. aeruginosa and S. aureus where SPI009 exhibited effective biofilm inhibition and eradication. Caenorhabditis elegans infected with P. aeruginosa also showed a significant improvement in survival when SPI009 was added to conventional antibiotic treatment. Overall, we demonstrate that SPI009, initially discovered as an anti-persister molecule in P. aeruginosa, possesses broad-spectrum activity and is highly suitable for the development of antibacterial combination therapies in the fight against chronic infections

Art-175 is a highly efficient antibacterial against multidrug-resistant strains and persisters of Pseudomonas aeruginosa

Artilysins constitute a novel class of efficient enzyme-based antibacterials. Specifically, they covalently combine a bacteriophage-encoded endolysin, which degrades the peptidoglycan, with a targeting peptide that transports the endolysin through the outer membrane of Gram-negative bacteria. Art-085, as well as Art-175, its optimized homolog with increased thermostability, are each composed of the sheep myeloid 29-amino acid (SMAP-29) peptide fused to the KZ144 endolysin. In contrast to KZ144, Art-085 and Art-175 pass the outer membrane and kill Pseudomonas aeruginosa, including multidrug-resistant strains, in a rapid and efficient (similar to 5 log units) manner. Time-lapse microscopy confirms that Art-175 punctures the peptidoglycan layer within 1 min, inducing a bulging membrane and complete lysis. Art-175 is highly refractory to resistance development by naturally occurring mutations. In addition, the resistance mechanisms against 21 therapeutically used antibiotics do not show cross-resistance to Art-175. Since Art-175 does not require an active metabolism for its activity, it has a superior bactericidal effect against P. aeruginosa persisters (up to > 4 log units compared to that of the untreated controls). In summary, Art-175 is a novel antibacterial that is well suited for a broad range of applications in hygiene and veterinary and human medicine, with a unique potential to target persister-driven chronic infections

Developmental Reaction Norms for Water Stressed Seedlings of Succulent Cacti

Succulent cacti are remarkable plants with capabilities to withstand long periods of drought. However, their adult success is contingent on the early seedling stages, when plants are highly susceptible to the environment. To better understand their early coping strategies in a challenging environment, two developmental aspects (anatomy and morphology) in Polaskia chichipe and Echinocactus platyacanthus were studied in the context of developmental reaction norms under drought conditions. The morphology was evaluated using landmark based morphometrics and Principal Component Analysis, which gave three main trends of the variation in each species. The anatomy was quantified as number and area of xylem vessels. The quantitative relationship between morphology and anatomy in early stages of development, as a response to drought was revealed in these two species. Qualitatively, collapsible cells and collapsible parenchyma tissue were observed in seedlings of both species, more often in those subjected to water stress. These tissues were located inside the epidermis, resembling a web of collapsible-cell groups surrounding turgid cells, vascular bundles, and spanned across the pith. Occasionally the groups formed a continuum stretching from the epidermis towards the vasculature. Integrating the morphology and the anatomy in a developmental context as a response to environmental conditions provides a better understanding of the organism's dynamics, adaptation, and plasticity

Perlindungan Konsumen Undang-Undang No.8 tahun 1999 terhadap Pelecehan oleh Mitra Grab Jasa Transportaasi Online

Hasil penelitian ini menunjukkan bahwa masyarakat dapat memahami terkait dengan perlindungan konsumen atas pelecehan seksual yang terjadi pada konsumen pengguna jasa transportasi online. Dan terhadap pelaku pelecehan seksual teersebut dapat dihukum dengan ketentuan hukum yang berlaku serta dapat diberikan sanksi oleh pihak perusahaan berupa pembekuan akun mitra bahkan bisa saja sampai pada putus mitra sesuai dengan kode etik perusahaan jasa transportasi online

Preclinical assessment of a propanol-amine derivative as a novel anti-persister molecule candidate for antibacterial co-therapy

The increasing rate of antibiotic resistance, together with the limited number of novel antibacterial compounds, is causing a true public health crisis where treatment options for patients infected with multidrug-resistant bacteria are down to only a few last-line antibiotics. Greatly contributing to the difficult treatment of these bacterial infections is the presence of a small fraction of persister cells; phenotypical variants which are highly tolerant to antibiotic treatment. Persister cells are responsible for the recalcitrant nature of chronic infections, contribute significantly to the antibiotic tolerance of biofilms and evidence is mounting that persister cells may serve as a reservoir for the development of antibiotic resistance. Clearly, there is an urgent need for novel therapies that allow the treatment of multidrug-resistant infections while effectively clearing the antibiotic-tolerant persister fraction. Despite the increasing insights into the molecular mechanisms behind persistence, their apparent redundancy and species-specific mechanisms are hampering the rational development of targeted anti-persister therapies. One possible way to circumvent this is the use of screenings specifically directed towards non-dividing cells, allowing the identification of novel anti-persister compounds from large chemical libraries. Previous research within the SPI group successfully used this top-down approach to identify SPI009, a propanol-amine derivative capable of decreasing the persister fraction of Pseudomonas aeruginosa in combination with the conventional antibiotic ofloxacin. This doctoral research project focused on the further characterization of this novel compound and the determination of its mechanism of action. While originally identified in a screening against P. aeruginosa, extensive in vitro testing revealed the ability of SPI009 to directly kill persister cells of several clinically relevant pathogens, including the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa and Enterobacter spp.), Burkholderia cenocepacia and the model organism Escherichia coli. Additionally, the observed antibiotic-independent effect of SPI009 allows successful combination with antibiotics from mechanistically distinct classes to further increase antibacterial activity. SPI009 showed capable of sensitizing bacteria to antibiotic treatment and, strikingly, restores antibiotic sensitivity even in (multidrug) resistant strains. The use of several in vitro set-ups revealed a potent anti-biofilm activity and ability of SPI009 to eradicate intracellular infections while the first in vivo tests demonstrated a significant increase in Caenorhabditis elegans survival upon treatment with the combination therapy of SPI009 and ciprofloxacin. These characteristics greatly increase the clinical potential of our compound as SPI009-based combination therapies have the potential to be employed in a great variety of bacterial infections. In a second part of this project, we aimed to unravel the mechanism of action of SPI009. This is not only essential for future clinical development but may also increase our knowledge about persister cells and ways to eradicate them, thereby contributing to the development of future anti-persister therapies. A combination of molecular-genetic and cellular approaches was used to demonstrate that SPI009 is capable of directly killing both persister and non-persister cells through extensive membrane damage. High levels of membrane damage result in cell lysis while intermediate permeabilization can significantly increase the sensitivity towards different antibiotics, confirming the potential of SPI009 as a candidate for antibacterial combination therapies. Within the frame of this PhD, we also explored the anti-persister effects of Art-175 in P. aeruginosa and A. baumannii. Artilysin s are comprised of a bacteriophage-produced endolysin coupled to a lipopolysaccharide-destabilizing peptide, allowing lysis of Gram-negative cells and, as such, possessing potential anti-persister activity. The demonstrated ability of Art-175 to quickly kill both normal and persister cells makes it an attractive alternative anti-persister therapy to treat bacterial infections in a highly specific manner. Overall, this PhD project contributes to the development of novel anti-persister therapies through the exploration of the previously described Art-175 as a potential anti-persister strategy and the detailed and extensive characterization and determination of the mechanism of action of the novel anti-persister molecule SPI009. While there are still some hurdles to overcome in the further clinical development of SPI009, this novel compound shows good potential and may serve as a scaffold for the development of future anti-persister therapies.nrpages: 222status: publishe

An Examination Of Emotion In Social And Cognitive Processes

Chapter 1 compared two lines of research that have examined the effects of cognitive load on emotions. One has shown that the emotions elicited by passive viewing of emotional images are reduced by cognitive load. Another has shown that, when maintained, emotions are not reduced by cognitive load. Participants either passively viewed, or maintained the emotions elicited by, negative emotional images, and after a delay rated their emotional intensity. Half of trials included cognitive load during the delay. Results showed cognitive load reduced emotional intensity during passive-viewing, but not during emotion maintenance. The present study replicates the both previous findings, showing the key factor is whether or not emotions are maintained. Chapter 1's results suggested high trait positive affect may be associated with higher intensity negative emotions, relative to low trait positive affect. Chapter 2 tested this idea with data from two samples. Participants self-reported either state-level (Sample 1) or trait-level affect (Sample 2). Then each participant performed a task that involved viewing negative emotional images, and rating the images' emotional intensity. Results indicated both state negative affect (Sample 1) and trait positive affect (Sample 2) correlated positively with image intensity ratings. The state negative affect finding is consistent with previous mood congruence research. The trait positive affect finding is consistent with Chapter 1, though a full understanding will require further research. Chapter 3 evaluated whether the shortage of Millennial students pursuing STEM is associated with their preference for work/life-interaction-a preference inconsistent with traditional science careers. We created two lab recruitment videos depicting contrasting approaches to running STEM labs and training students: A work-focused video and a work/life-interaction-focused video. In Study 3.1, current professors rated the videos, and confirmed the two videos reflected real-world differences in training approaches. In Study 3.2, current STEM students watched one of the two videos, and completed surveys. The work/life-interaction-focused video participants reported a greater sense of belonging to and desire to participate in the lab, relative to the work-focused video participants. This suggests Millennials possess a strong desire for work/life-interaction, which runs counter to the traditional lab-training model

Evaluation de la satisfaction de consommateurs lambda : cas Brussels Beer Project

Notre mémoire concerne les consommateurs lambda qui ne participent pas au crowdfunding et à la co-création des bières de la brasserie Brussels Beer Project. Cette nouvelle brasserie a comme particularité de proposer une gamme de bières éphémères tout en proposant une gamme permanente. L’objectif de ce mémoire est de connaître la satisfaction des consommateurs par rapport à l’offre de cet établissement (bière, service, merchandising). Notre intérêt s’est porté sur les consommateurs qui se rendent à la tap room pour y déguster des bières et non sur ceux qui les achètent pour une dégustation ultérieure. Un guide d’entretien nous a servi de support lors d’une entrevue avec l’un des dirigeants. Afin de recueillir plus d’informations sur la perception de ces bières, nous avons aussi mené une pré-enquête qualitative. Grâce aux informations recueillies, nous avons pu cerner l’environnement de production et de commercialisation dans un premier temps. La réalisation de cette mission a nécessité dans un second temps, la mise en commun des diverses informations en vue de déterminer les critères de satisfaction. Nous avons pu exposer quelques éléments déterminants la satisfaction des consommateurs tels que les processus cognitifs ou bien affectifs, le capital marque, la qualité perçue, etc. Grâce à toutes ces démarches, nous avons établi une méthodologie de recherche et déterminé deux hypothèses : H1 : En général, les consommateurs lambda sont satisfaits des offres de BBP H2 : Les critères pouvant déterminer la satisfaction globale des consommateurs de BBP sont : le nombre de bières consommées, la qualité des produits, la diversité de l’offre, le goût et l’expérience. Celles-ci ont donné naissance à un questionnaire que nous avons administré à 21 consommateurs. Nous avons opté pour une démarche déductive. Nous nous sommes servis du logiciel « Sphinx Declic 2 » afin d’analyser les données de notre recherche. Le but étant d’interpréter nos résultats et d’établir une discussion pertinente quant à nos deux hypothèses. Nous avons pu confirmer H1 et infirmer H2. La satisfaction globale dépendrait essentiellement de la qualité des produits et de l’expérience vécue. Pour terminer, nous avons conclu notre travail en mettant en avant le fait que ces bières sont de qualité et, de ce fait, contribuent en grande partie à la satisfaction des consommateurs ordinaires de la tap room de Brussels Beer Project.Master [120] en ingénieur de gestion (Mons), Université catholique de Louvain, 2018La diffusion de ce mémoire n'est pas autorisée par l'institutio

Développement d’une intervention de déprescription médiée par le médecin traitant : consensus d’experts par une méthode Delphi abaque

Introduction. Le vieillissement de la population française engendre une polymédication, aux lourdes conséquences humaines et économiques. La déprescription semble être un outil à explorer pour réduire la iatrogénie. Les interventions médiées par le médecin traitant sont peu étudiées dans la littérature scientifique, alors qu’il semble être un levier majeur de la déprescription pour les patients. C’est pourquoi l’objectif principal de notre étude était d’intégrer le médecin traitant dans une intervention de déprescription, pour ses patients âgés polymédiqués. Nous avons aussi souhaité savoir si une consultation dédiée à la déprescription pouvait être utile pour les médecins. Matériel et Méthodes. Nous avons utilisé une méthode Delphi abaque afin de répondre à notre question de recherche. Nous avons souhaité 4 niveaux d’expertise : de terrain, pharmacologique, des spécialistes et théorique, permettant ainsi de recruter 18 experts. Un pré-questionnaire et trois questionnaires successifs leur ont été proposés d’août 2021 à janvier 2022. Résultats. Notre étude a permis de déterminer au total 60 consensus favorables autour de cinq thèmes principaux : la formation théorique pour le médecin traitant ; une consultation dédiée à la déprescription ; une concertation pluri-professionnelle ; un bilan de médication ; les différents facteurs d’influence de la déprescription. Ainsi, nos experts se sont accordés sur l’importance d’une formation à la déprescription pour le médecin, avant toute intervention auprès du patient. La consultation dédiée ne semble pas, quant à elle, être une solution à part entière : la déprescription doit être abordée lors des consultations de renouvellement du médecin généraliste. Elle pourra par contre être proposée dans certaines situations plus complexes. En outre, la concertation pluri-professionnelle doit prendre en compte tous les acteurs de santé qui suivent le patient. Le bilan de médication partagé peut être proposé à la fois par le médecin traitant et par le pharmacien. Enfin, il existe de nombreux moyens de favoriser la déprescription : mieux communiquer sur sa faisabilité auprès des professionnels et de la population générale, impliquer le patient avec l’éducation thérapeutique, ou encore privilégier les alternatives à la seule réponse médicamenteuse. Conclusion. La mise en œuvre des propositions consensuelles de cette étude pourrait avoir un impact direct sur la prise en charge des patients de plus de 65 ans polymédiqués en médecine générale, tant du point de vue des patients que des médecins généralistes