Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics.

Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically contain a target protein ligand linked to an E3 ligase ligand, recruit a target protein to the E3 ligase to induce its ubiquitination and degradation. Here, we applied PROTAC approaches to develop broad-spectrum antivirals targeting key host factors for many viruses and virus-specific antivirals targeting unique viral proteins. For host-directed antivirals, we identified a small-molecule degrader, FM-74-103, that elicits selective degradation of human GSPT1, a translation termination factor. FM-74-103-mediated GSPT1 degradation inhibits both RNA and DNA viruses. Among virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). As a proof of principle, RNA mimics of viral promoter sequences were used as heterobifunctional molecules to recruit and target influenza viral polymerase for degradation. This work highlights the broad utility of TPD to rationally design and develop next-generation antivirals

LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects

Toll-like receptors (TLRs) are the principal mediators of rapid microbial recognition: the lipopolysaccharide (LPS) receptor TLR4 seems to have a paradigmatic role. Single nucleotide polymorphisms (SNPs) in the TLR4 gene, such as +896A/G, known to attenuate receptor signaling, have been described. The +896A/G SNP is significantly less frequent in patients with myocardial infarction, Alzheimer’s disease or prostate cancer, whereas it is overrepresented in centenarians. To clarify and confirm the biological effects of +896A/G SNP and its role in the pathophysiology of age-related diseases and longevity, we assessed the levels of IL-6, TNF-a, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of this SNP. To evaluate the possible influence of SNPs in PTGS2 and 5-Lo genes on eicosanoid production, the enrolled individuals were also genotyped for 765G/C PTGS2 and 1708G/A 5-Lo SNPs. Both pro-inflammatory cytokines and eicosanoids were significantly lower in carriers bearing the TLR4 mutation, whereas the antiinflammatory IL-10 values were higher. On the basis of data reported herein, some suggestions can be drawn. First, pathogen load, by interacting with the host genotype, determines the type and intensity of inflammatory responses, according to the pro-inflammatory status and tissue injury, implicated in the pathophysiology of major age-related diseases. Second, adequate control of inflammatory response might reduce the risk of these diseases, and, reciprocally, might increase the chance of extended survival in an environment with reduced antigen (that is, pathogen) load

Self-reported health status and access to health services in a sample of prisoners in Italy

<p>Abstract</p> <p>Background</p> <p>Self-reported health status in underserved population of prisoners has not been extensively explored. The purposes of this cross-sectional study were to assess self-reported health, quality of life, and access to health services in a sample of male prisoners of Italy.</p> <p>Methods</p> <p>A total of 908 prisoners received a self-administered anonymous questionnaire pertaining on demographic and detention characteristics, self-reported health status and quality of life, access to health services, lifestyles, and participation to preventive, social, and rehabilitation programs. A total of 650 prisoners agreed to participate in the study and returned the questionnaire.</p> <p>Results</p> <p>Respectively, 31.6% and 43.5% of prisoners reported a poor perceived health status and a poor quality of life, and 60% admitted that their health was worsened or greatly worsened during the prison stay. Older age, lower education, psychiatric disorders, self-reported health problems on prison entry, and suicide attempts within prison were significantly associated with a perceived worse health status. At the time of the questionnaire delivery, 30% of the prisoners self-reported a health problem present on prison entry and 82% present at the time of the survey. Most frequently reported health problems included dental health problems, arthritis or joint pain, eye problems, gastrointestinal diseases, emotional problems, and high blood pressure. On average, prisoners encountered general practitioners six times during the previous year, and the frequency of medical encounters was significantly associated with older age, sentenced prisoners, psychiatric disorders, and self-reported health problems on prison entry.</p> <p>Conclusions</p> <p>The findings suggest that prisoners have a perceived poor health status, specific care needs and health promotion programs are seldom offered. Programs for correction of risk behaviour and prevention of long-term effects of incarceration on prisoners' health are strongly needed.</p

Paget disease of bone-associated UBA domain mutations of SQSTM1 exerts distinct effects on protein structure and function

SQSTM1 mutations are common in patients with Paget disease of bone (PDB), with most affecting the C-terminal ubiquitin-associated (UBA) domain of the SQSTM1 protein. We performed structural and functional analyses of two UBA domain mutations, an I424S mutation relatively common in UK PDB patients, and an A427D mutation associated with a severe phenotype in Southern Italian patients. Both impaired SQSTM1's ubiquitin-binding function in pull-down assays and resulted in activation of basal NF-kappa B signalling, compared to wild-type, in reporter assays. We found evidence for a relationship between the ability of different UBA domain mutants to activate NF-kappa B signalling in vitro and number of affected sites in vivo in 1152 PDB patients from the UK and Italy, with A427D-SQSTM1 producing the greatest level of activation (relative to wild-type) of all PDB mutants tested to date. NMR and isothermal titration calorimetry studies were able to demonstrate that I424S is associated with global structural changes in the UBA domain, resulting in 10-fold weaker UBA dimer stability than wild-type and reduced ubiquitin-binding affinity of the UBA monomer. Our observations provide insights into the role of SQSTM1-mediated NF-kappa B signalling in PDB aetiology, and demonstrate that different mutations in close proximity within loop 2/helix 3 of the SQSTM1 UBA domain exert distinct effects on protein structure and stability, including indirect effects at the UBA/ubiquitin-binding interfac

Civiltà della Campania. Anno III, n. 4 (gennaio-marzo 1976)

A. III, n. 4 (gennaio-marzo 1976): Ricordo di Alfonso, P. 3 ; A. Gatto, Un sodalizio d’arte sotto lo stesso cielo, P. 4 ; R. Causa, Itinerari nell’arte catalana, P. 12 ; B. Gatta, Un altro inglese che ama Garibaldi, P. 18 ; A. Garzya, Napoli e Bisanzio, P. 26 ; S. Ferraretti, Il grande Archivio Napoletano, P. 32 ; B.G., L’Abate Galiani tra Napoli e Parigi, P. 34 ; M. Stefanile, Campania a tavola, P. 36 ; D. Rea, Pulcinella: il mistero di una maschera, P. 44 ; L. Compagnone, Il piccolo teatro di Raffaele Petra, P. 56 ; V. Ricciuti, Quando il cinema si chiamava Napoli, P. 58 ; R. Cantarella, C’era una volta una piccola città, P. 62 ; E. Mallardo, La cattedrale di Avellino, P. 66 ; V. Gramignazzi-Serrone, S. Guglielmo al Goleto, P. 70 ; F. de Ciuceis, I fasti del San Carlo, P. 78 ; L. Orsini, Faito una selva nel cielo, P. 82 ; S. Ferraro, Archeologia a Sorrento, P. 86 ; G. Blasi, Un parco negli Alburni, P. 88 ; D. Lanzara, Il convento di Ischia, P. 92 ; Notiziario, P. 93

Bone density and genomic analysis unfold cold adaptation mechanisms of ancient inhabitants of Tierra del Fuego

The Fuegians, ancient inhabitants of Tierra del Fuego, are an exemplary case of a cold-adapted population, since they were capable of living in extreme climatic conditions without any adequate clothing. However, the mechanisms of their extraordinary resistance to cold remain enigmatic. Brown adipose tissue (BAT) plays a crucial role in this kind of adaptation, besides having a protective role on the detrimental effect of low temperatures on bone structure. Skeletal remains of 12 adult Fuegians, collected in the second half of XIX century, were analyzed for bone mineral density and structure. We show that, despite the unfavorable climate, bone mineral density of Fuegians was close to that seen in modern humans living in temperate zones. Furthermore, we report significant differences between Fuegians and other cold-adapted populations in the frequency of the Homeobox protein Hox-C4 (HOXC4) rs190771160 variant, a gene involved in BAT differentiation, whose identified variant is predicted to upregulate HOXC4 expression. Greater BAT accumulation might therefore explain the Fuegians extreme cold-resistance and the protection against major cold-related damage. These results increase our understanding of how ecological challenges have been important drivers of human–environment interactions during Humankind history

Civiltà della Campania. Anno II, n. 3 (agosto-ottobre 1975)

A. II, n.3 (agosto-ottobre 1975): Il messaggio dell’Assessore Emilio de Feo, P. 3 ; M. Parrilli, Continuità nel turismo regionale, P. 3 ; Napoli nei secoli, P. 5 ; G. Galasso, Tumulti ed elezioni del ’600, P. 6 ; N. Cilento, Nella città medioevale, P. 18 ; B. Gatta, Capri tra Napoleone e Murat, P. 24 ; R. Causa, Gioacchino Toma a Napoli, P. 30 ; A. Assante, Napoli e il suo porto, P. 34 ; G. Grimaldi, Messaggio di fede dell’Anno Santo, P. 40 ; R. Vlad, Musica all’aperto, P. 50 ; M. Stefanile, Viaggio nella storia di Amalfi, P. 52 ; D. Rea, Mappa minore, P. 60 ; M. Prisco , Incontro con la Badia, P. 68 ; P. Amos e A. Gambardella, Il villaggio di Albori, P. 74 ; R. Virtuoso, Giovanni Cuomo ritorna tra i giovani, P. 76 ; V. Panebianco, Il turismo venuto dalla storia, P. 80 ; A.P. Carbone, Le grotte di Pertosa, P. 84 ; F. de Ciuceis, Il mare di Caserta, P. 88 ; E. Tirone, Riti settennali a Guardia Sanframondi, P. 92 ; F. Calabro, Turismo e cultura a Capri, P. 98 ; F. de Ciuceis, Settembre al Borgo, P. 102 ; I. Santoro, Teggiano citta museo, P. 104 ; Notiziario, P. 108

Civiltà della Campania. Anno I, n. 1 (dicembre 1974)

A.I, n. 1 (dicembre 1974): M. Parrilli, Editoriale, P. 3 ; R. Virtuoso, Civiltà della Campania, P. 3 ; G. Galasso, Fisionomìa storica della regione, P. 6 ; Natale in Campania, P. 11, R. Causa, Cinque secoli di Presepe di, P. 12 ; M. Stefanile, I presepi d’una volta di, P. 20 ; D. Rea, L’universo mangereccio del Presepe di, P. 28 ; M. Prisco, Il presepe in provincia di, P. 34 ; B. Gatta, Una storia che non fu, P. 42 ; A. Mozzillo, Stendhal a Napoli, P. 47 ; E. Perrin, Viaggio a Cava d’un abate francese, P. 52 ; A.P. Carbone, Ravello: Villa Rufolo un paradiso per tutti, 54 ; D. Fernandez, Lettera d’amore a Napoli, P. 60 ; A. Gatto, Un mazzetto di poesie con la mia mano, 54 ; M. Parrilli, Vocazione turistica e culturale del Salernitano, P. 60 ; E. Comito, Poesia di Casertantica, P. 64 ; A. Fratta, Majorca e le Sirene, P. 67 ; V. Ricciuti, De Sica addio, P. 72 ; M. Perrotta, Il motoscafo spazzino del mare di Capri, P. 76 ; F. Canessa, Ritorna l’« opera buffa », P. 78 ; P. Gargano, Archeologia in villa, P. 83 ; E. Corsi, Per un nuovo equilibrio alberghiero, P. 86 ; F. Garbaccio, Un termalismo per tutte le stagioni, P. 88; G. Blasi, Amalfi by night, P. 90 ; A. Scelzo, La maratona Paestum-Salerno, P. 91 ; Notiziario, P. 92 ; F. De Ciuceis, Segnalazioni bibliografiche, P. 95

Structured reporting for fibrosing lung disease: a model shared by radiologist and pulmonologist

Objectives: To apply the Delphi exercise with iterative involvement of radiologists and pulmonologists with the aim of defining a structured reporting template for high-resolution computed tomography (HRCT) of patients with fibrosing lung disease (FLD). Methods: The writing committee selected the HRCT criteria\ue2\u80\u94the Delphi items\ue2\u80\u94for rating from both radiology panelists (RP) and pulmonology panelists (PP). The Delphi items were first rated by RPs as \ue2\u80\u9cessential\ue2\u80\u9d, \ue2\u80\u9coptional\ue2\u80\u9d, or \ue2\u80\u9cnot relevant\ue2\u80\u9d. The items rated \ue2\u80\u9cessential\ue2\u80\u9d by &lt; 80% of the RP were selected for the PP rating. The format of reporting was rated by both RP and PP. Results: A total of 42 RPs and 12 PPs participated to the survey. In both Delphi round 1 and 2, 10/27 (37.7%) items were rated \ue2\u80\u9cessential\ue2\u80\u9d by more than 80% of RP. The remaining 17/27 (63.3%) items were rated by the PP in round 3, with 2/17 items (11.7%) rated \ue2\u80\u9cessential\ue2\u80\u9d by the PP. PP proposed additional items for conclusion domain, which were rated by RPs in the fourth round. Poor consensus was observed for the format of reporting. Conclusions: This study provides a template for structured report of FLD that features essential items as agreed by expert thoracic radiologists and pulmonologists