Design and Synthesis of 4-Alkylidene-b-lactams: Benzyland Phenethyl-carbamates as Key Fragments to Switch on Antibacterial Activity

The emergence of multidrug-resistant bacterial strains is particularly important in chronic pathologies such as cystic fibrosis (CF), in which persistent colonization and selection of resistant strains is favored by the frequent and repeated use of antibacterial agents. Staphylococcus aureus is a common pathogen in CF patients that has an associated increased multidrug resistance. In previous studies we demonstrated that the presence of a 4-alkylidene side chain directly linked to a beta-lactam appeared to strengthen the potency against S. aureus, especially against methicillin-resistant S. aureus (MRSA) strains. In the present study, 21 new 4-alkylidene-beta-lactams were synthesized and evaluated for antibacterial activity. We designed the new compounds to have aryl, benzyl, or phenethyl-carbamate groups on the C3 hydroxyethyl side chain. We found a correlation between biological activity and the nitrogen substituent of the carbamate group, and two phenethyl-carbamate b-lactams were shown to be valuable antibacterial agents against selected linezolid-resistant strains, with a minimum inhibitory concentrations of 2–4 mgL-1

Leukocyte Integrin Antagonists as a Novel Option to Treat Dry Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a complex multifactorial degenerative disease that leads to irreversible blindness. AMD affects the macula, the central part of the retina responsible for sharp central vision. Retinal pigment epithelium (RPE) is the main cellular type affected in dry AMD. RPE cells form a monolayer between the choroid and the neuroretina and are in close functional relationship with photoreceptors; moreover, RPE cells are part of the blood retina barrier that is disrupted in ocular diseases such as AMD. During ocular inflammation lymphocytes and macrophages are recruited, contact RPE and produce pro-inflammatory cytokines, which play an important role in AMD pathogenesis. The interaction between RPE and immune cells is mediated by leukocyte integrins, heterodimeric transmembrane receptors, and adhesion molecules, including VCAM-1 and ICAM-1. Within this frame, this study aimed to characterize RPE-leukocytes interaction and to investigate any potentially beneficial effects induced by integrin antagonists (DS-70, MN27 and SR714), developed in previous studies. ARPE-19 cells were co-cultured for different incubation times with Jurkat cells and apoptosis and necrosis levels were analyzed by flow cytometry. Moreover, we measured the mRNA levels of the pro-inflammatory cytokine IL-1\u3b2 and the expression of adhesion molecules VCAM-1 and ICAM-1. We found that RPE-lymphocyte interaction increased apoptosis and necrosis levels in RPE cells and the expression of IL-1\u3b2. This interaction was mediated by the binding of \u3b14\u3b21 and \u3b1L\u3b22 integrins to VCAM-1 and ICAM-1, respectively. The blockade of RPE-lymphocyte interaction with blocking antibodies highlighted the pivotal role played by integrins. Therefore, \u3b14\u3b21 and \u3b1L\u3b22 integrin antagonists were employed to disrupt RPE-lymphocyte crosstalk. Small molecule integrin antagonists proved to be effective in reducing RPE cell death and expression of IL-1\u3b2, demonstrating that integrin antagonists could protect RPE cells from detrimental effects induced by the interaction with immune cells recruited to the retina. Overall, the leukocyte integrin antagonists employed in the present study may represent a novel opportunity to develop new drugs to fight dry AMD

“Don’t blame the shopkeeper!!” Food, drink and confectionery advertising and British Government market controls during the Second World War

A novel series of \u3b2-lactam derivatives that was designed and synthesized to target RGD-binding and leukocyte integrins is reported. The compound library was evaluated by investigating the effects on integrin-mediated cell adhesion and cell signaling in cell lines expressing \u3b1v\u3b23, \u3b1v\u3b25, \u3b1v\u3b26, \u3b15\u3b21, \u3b1IIb\u3b23, \u3b14\u3b21, and \u3b1L\u3b22 integrins. SAR analysis of the new series of azetidinones enabled the recognition of structural elements associated with integrin selectivity. We obtained selective and potent agonists that could induce cell adhesion and promote cell signaling mediated by \u3b1v\u3b23, \u3b1v\u3b25, \u3b15\u3b21, or \u3b14\u3b21 integrin, and antagonists for the integrins \u3b1v\u3b23 and \u3b15\u3b21, as well as \u3b14\u3b21 and \u3b1L\u3b22, preventing the effects elicited by the respective endogenous agonists

Impact of Mycobacterium tuberculosis RD1-locus on human primary dendritic cell immune functions

Modern strategies to develop vaccines against Mycobacterium tuberculosis (Mtb) aim to improve the current Bacillus Calmette-Guerin (BCG) vaccine or to attenuate the virulence of Mtb vaccine candidates. In the present study, the impact of wild type or mutated region of difference 1 (RD1) variants on the immunogenicity of Mtb and BCG recombinants was investigated in human primary dendritic cells (DC). A comparative analysis of transcriptome, signalling pathway activation, maturation, apoptosis, cytokine production and capacity to promote Th1 responses demonstrated that DC sense quantitative and qualitative differences in the expression of RD1-encoded factors - ESAT6 and CFP10 - within BCG or Mtb backgrounds. Expansion of IFN-γ producing T cells was promoted by BCG::RD1-challenged DC, as compared to their BCG-infected counterparts. Although Mtb recombinants acted as a strong Th-1 promoting stimulus, even with RD1 deletion, the attenuated Mtb strain carrying a C-terminus truncated ESAT-6 elicited a robust Th1 promoting phenotype in DC. Collectively, these studies indicate a necessary but not sufficient role for the RD1 locus in promoting DC immune-regulatory functions. Additional mycobacterial factors are likely required to endow DC with a high Th1 polarizing capacity, a desirable attribute for a successful control of Mtb infection

“Destinazione Futuro”, un esperimento INAF di riflessione condivisa riguardo il tempo che verrà. Report edizione anno 2021

Il 21 maggio del 2021, in occasione dell’avvicinarsi di due importanti ricorrenze a cavallo tra scienza e fantascienza (in agosto dell’anno ricorre il centenario dalla nascita di Gene Roddenberry, creatore di Star Trek e il ventennale dalla morte di Fred Hoyle, celebre scienziato e scrittore di fantascienza) si è lanciato un progetto per ascoltare il grande pubblico su una serie di questioni riguardanti la visione personale del futuro, mantenendo un registro intermedio tra scienza e fantascienza. Le risposte pervenute (frutto di più di duecento compilazioni) sono state valutate dagli organizzatori e in parte condivise con alcuni esperti in varie discipline, che sono stati intervistati per una serie di articoli pubblicati - uno alla settimana - durante l’estate 2021 sulla testata EduINAF. L’iniziativa si inserisce in un dialogo tra INAF e il pubblico più vasto, che in un periodo assai critico - a motivo delle restrizioni causate dalla pandemia COVID19 - ha potuto esprimere le proprie speranze e anche i disagi, ritrovando un Ente in ascolto e non chiuso nel proprio sapere, che anzi ha fatto degli input del pubblico uno strumento di ulteriore lavoro con selezionati esperti. Considerata la risposta molto positiva e il buon numero di compilazioni del questionario, si concorda di lasciare aperta la possibilità di produrre ulteriori interviste, contattando successivamente altri esperti, in modo che i dati raccolti possano venire usati in modi ancora diversi, accogliendo gli spunti che essi offrono per un lavoro capace di condurre in innumerevoli direzioni, molte delle quali ancora inesplorate

Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application?

Nerve growth factor (NGF) was the first-discovered member of the neurotrophin family, a class of bioactive molecules which exerts powerful biological effects on the CNS and other peripheral tissues, not only during development, but also during adulthood. While these molecules have long been regarded as potential drugs to combat acute and chronic neurodegenerative processes, as evidenced by the extensive data on their neuroprotective properties, their clinical application has been hindered by their unexpected side effects, as well as by difficulties in defining appropriate dosing and administration strategies. This paper reviews aspects related to the endogenous production of NGF in healthy and pathological conditions, along with conventional and biomaterial-assisted delivery strategies, in an attempt to clarify the impediments to the clinical application of this powerful molecule

"A Gianni Rodari, via Lattea quaraquarinci". Report della seconda edizione del Concorso INAF di scrittura per bambini (anno 2021-2022)

Il 23 ottobre 2021, l’Istituto Nazionale di Astrofisica (INAF) ha lanciato la seconda edizione del Concorso di scrittura a tema astronomico ispirato a Gianni Rodari, “A Gianni Rodari, via Lattea quaraquarinci”. Il Concorso, a cura del Gruppo Storie dell’INAF e in collaborazione con EduINAF, è rivolto agli studenti della scuola primaria e secondaria di primo grado (6-13 anni). In questa seconda edizione, il Concorso ha aperto le porte alla partecipazione di classe oltre a quella individuale, ricevendo 168 opere individuali e 44 di classe. Come nella prima edizione, l’accoglienza è stata estremamente calorosa, i giovani partecipanti – e in generale il loro contesto scolastico e famigliare – hanno risposto positivamente e con entusiasmo alla sfida. La collaborazione del Concorso con i progetti dell’INAF PRISMA e Sorvegliati Spaziali ha portato alla scelta del tema dell’edizione che quest’anno ha riguardato gli “Asteroidi e altri sorvegliati spaziali”. La seconda edizione ha goduto di un aumento di personale INAF nel gruppo di lavoro del Concorso, permettendo un più efficace divisione dei ruoli e del carico di lavoro: persone di diversi profili e sedi dell’INAF hanno collaborato fra loro e con professionalità esterne quali Emanuela Bussolati (autrice e illustratrice per l’infanzia), Cesare Sottocorno (docente) e Francesca Poppi (illustratrice, graphic e web designer). In questo Report sono discussi i punti salienti della seconda edizione del Concorso, un confronto con la prima edizione e le criticità rilevate