Polyphenolic C-glucosidic ellagitannins present in oak-aged wine inhibit HIV-1 nucleocapsid protein

HIV-1 nucleocapsid protein (NC) is a nucleic acid chaperone implicated in several steps of the virus replication cycle and an attractive new target for drug development. In reverse transcription, NC destabilizes nucleic acid secondary structures and catalyzes the annealing of HIV-1 TAR RNA to its DNA copy (cTAR) to form the heteroduplex TAR/cTAR. A screening program led to the identification of the plant polyphenols acutissimins A and B as potent inhibitors of NC in different assays. These two flavano-ellagitannins, which are found in wine aged in oak barrels, exhibited different mechanisms of protein inhibition and higher potency relatively to their epimers, epiacutissimins A and B, and to simpler structures notably representing hydrolytic fragments and metabolites therefrom

Mechanisms of HIV-1 Nucleocapsid Protein Inhibition by Lysyl-Peptidyl-Anthraquinone Conjugates

The Nucleocapsid protein NCp7 (NC) is a nucleic acid chaperone responsible for essential steps of the HIV-1 life cycle and an attractive candidate for drug development. NC destabilizes nucleic acid structures and promotes the formation of annealed substrates for HIV-1 reverse transcription elongation. Short helical nucleic acid segments bordered by bulges and loops, such as the Trans-Activation Response element (TAR) of HIV-1 and its complementary sequence (cTAR), are nucleation elements for helix destabilization by NC and also preferred recognition sites for threading intercalators. Inspired by these observations, we have recently demonstrated that 2,6-disubstituted peptidylanthraquinone-conjugates inhibit the chaperone activities of recombinant NC in vitro, and that inhibition correlates with the stabilization of TAR and cTAR stem-loop structures. We describe here enhanced NC inhibitory activity by novel conjugates that exhibit longer peptidyl chains ending with a conserved Nterminal lysine. Their efficient inhibition of TAR/cTAR annealing mediated by NC originates from the combination of at least three different mechanisms, namely, their stabilizing effects on nucleic acids dynamics by threading intercalation, their ability to target TAR RNA substrate leading to a direct competition with the protein for the same binding sites on TAR, and, finally, their effective binding to the NC protein. Our results suggest that these molecules may represent the stepping-stone for the future development of NC-inhibitors capable of targeting the protein itself and its recognition site in RNA

Experimental Implementation of A Quantum Zero-Knowledge Proof for User Authentication

A new interactive quantum zero-knowledge protocol for identity authentication implementable in currently available quantum cryptographic devices is proposed and demonstrated. The protocol design involves a verifier and a prover knowing a pre-shared secret, and the acceptance or rejection of the proof is determined by the quantum bit error rate. It has been implemented in modified Quantum Key Distribution devices executing two fundamental cases. In the first case, all players are honest, while in the second case, one of the users is a malicious player. We demonstrate an increase of the quantum bit error rate around 25% in the latter case compared to the case of honesty. The protocol has also been validated for distances from a back-to-back setup to more than 60 km between verifier and prover. The security and robustness of the protocol has been analysed, demonstrating its completeness, soundness and zero-knowledge properties

Anatomia da Madeira de Melia azedarach L. (Meliaceae)

A anatomia da madeira de Melia azedarach L. é descrita de acordo com IAWA (1989) e ilustrada com fotomicrografias, com base em material procedente de Jaguari, RS, Brasil. Na estrutura da madeira destacam-se: poros em múltiplos radiais; placas de perfuração simples; elementos vasculares pequenos; pontoações intervasculares pequenas, alternas e ornamentadas; parênquima axial vasicêntrico, confluente e marginal; raios homogêneos; e fibras libriformes não septadas

Suppression of Age-Related Salivary Gland Autoimmunity by Glycosylation-Dependent galectin-1-driven Immune Inhibitory Circuits

Aging elicits quantitative and qualitative changes in different immune components, leading to disruption of tolerogenic circuits and development of autoimmune disorders. Galectin-1 (Gal1), an endogenous glycan-binding protein, has emerged as a regulator of immune cell homeostasis by shaping the fate of myeloid and lymphoid cells. Here, we demonstrate that aged Gal1-null mutant (Lgals1−/−) mice develop a spontaneous inflammatory process in salivary glands that resembles Sjögren's syndrome. This spontaneous autoimmune phenotype was recapitulated in mice lacking β1,6N-acetylglucosaminyltransferase V (Mgat5), an enzyme responsible for generating β1,6-branched complex N-glycans, which serve as a major ligand for this lectin. Lack of Gal1 resulted in CD11c+ dendritic cells (DCs) with higher immunogenic potential, lower frequency of Foxp3+ regulatory T cells (Tregs), and increased number of CD8+ T cells with greater effector capacity. Supporting its tolerogenic activity, Gal1 expression decreased with age in autoimmunity-prone nonobese diabetic (NOD) mice. Treatment with recombinant Gal1 restored tolerogenic mechanisms and reduced salivary gland inflammation. Accordingly, labial biopsies from primary Sjögren's syndrome patients showed reduced Gal1 expression concomitant with higher number of infiltrating CD8+ T cells. Thus, endogenous Gal1 serves as a homeostatic rheostat that safeguards immune tolerance and prevents age-dependent development of spontaneous autoimmunity.Fil: Martínez Allo, Verónica Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Hauk, Vanesa Cintia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Sarbia, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Pinto, Nicolás Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Croci Russo, Diego Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Dalotto Moreno, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Morales, Rosa M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gatto, Sabrina Gisela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Manselle Cocco, Montana Nicolle. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Stupirski, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Deladoey, Ángel. Hospital Bernardino Rivadavia; ArgentinaFil: Maronna, Esteban. Sanatorio Mater Dei; ArgentinaFil: Marcaida, Priscila. Hospital Bernardino Rivadavia; ArgentinaFil: Durigan, Virginia. Hospital Bernardino Rivadavia; ArgentinaFil: Secco, Anastasia. Hospital Bernardino Rivadavia; ArgentinaFil: Mamani, Marta. Hospital Bernardino Rivadavia; ArgentinaFil: Santos, Alicia Dos. Hospital Bernardino Rivadavia; ArgentinaFil: Pellet, Antonio Catalán. Hospital Bernardino Rivadavia; ArgentinaFil: Leiros, Claudia Pérez. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Rabinovich, Gabriel Adrián. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Toscano, Marta Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

SARS-CoV-2-related bronchiolitis: a multicentre international study

Background: Bronchiolitis is the main acute lower respiratory tract infection in infants. Data regarding SARS-CoV-2-related bronchiolitis are limited. Objective: To describe the main clinical characteristics of infants with SARS-CoV-2-related bronchiolitis in comparison with infants with bronchiolitis associated with other viruses. Setting, patients, interventions: A multicentre retrospective study was conducted in 22 paediatric emergency departments (PED) in Europe and Israel. Infants diagnosed with bronchiolitis, who had a test for SARS-CoV-2 and were kept in clinical observation in the PED or admitted to hospital from 1 May 2021 to 28 February 2022 were considered eligible for participation. Demographic and clinical data, diagnostic tests, treatments and outcomes were collected. Main outcome measures: The main outcome was the need for respiratory support in infants testing positive for SARS-CoV-2 compared with infants testing negative. Results: 2004 infants with bronchiolitis were enrolled. Of these, 95 (4.7%) tested positive for SARS-CoV-2. Median age, gender, weight, history of prematurity and presence of comorbidities did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative infants. Human metapneumovirus and respiratory syncytial virus were the viruses most frequently detected in the group of infants negative for SARS-CoV-2.Infants testing positive for SARS-CoV-2 received oxygen supplementation less frequently compared with SARS-CoV-2-negative patients, 37 (39%) vs 1076 (56.4%), p=0.001, OR 0.49 (95% CI 0.32 to 0.75). They received less ventilatory support: 12 (12.6%) high flow nasal cannulae vs 468 (24.5%), p=0.01; 1 (1.0%) continuous positive airway pressure vs 125 (6.6%), p=0.03, OR 0.48 (95% CI 0.27 to 0.85). Conclusions: SARS-CoV-2 rarely causes bronchiolitis in infants. SARS-CoV-2-related bronchiolitis mostly has a mild clinical course

Association of extent of cannabis use and psychotic like intoxication experiences in a multi-national sample of first episode psychosis patients and controls

BackgroundFirst episode psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in patients and controls and whether this differs between groups.MethodsWe analysed data on patients who had ever used cannabis (n = 655) and controls who had ever used cannabis (n = 654) across 15 sites from six countries in the EU-GEI study (2010–2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use.ResultsCaseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences (p ⩽ 0.001). For psychotic-like experiences (PEs) there was a significant interaction for caseness × frequency of use (p 0.5).ConclusionsFEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher levels of cannabis use compared to controls. This suggests a specific psychotomimetic response in FEP patients related to heavy cannabis use. Clinicians should enquire regarding cannabis related PEs and advise that lower levels of cannabis use are associated with less frequent PEs

Prevalence of SARS-CoV-2 positivity in infants with bronchiolitis: a multicentre international study

Background Bronchiolitis is the leading acute respiratory tract infection in infants during the winter season. Since the beginning of the SARS-CoV-2 pandemic, a reduction in the number of bronchiolitis diagnoses has been registered. Objective The present study aimed to describe the incidence and clinical features of bronchiolitis during the 2020-2021 winter season in a large cohort of children in Europe and Israel, and to clarify the role of SARS-CoV-2. Setting, patients, interventions We conducted a multicentre observational cross-sectional study in 23 paediatric emergency departments in Europe and Israel. Clinical and demographic data about all the cases of infants diagnosed with bronchiolitis from 1 October 2020 to 30 April 2021 were collected. For each enrolled patient, diagnostic tests, treatments and outcomes were reported. Main outcome measures The main outcome was the prevalence of SARS-CoV-2-positive bronchiolitis. Results Three hundred and fourteen infants received a diagnosis of bronchiolitis during the study period. Among 535 infants who tested positive for SARS-CoV-2, 16 (3%) had bronchiolitis. Median age, male sex predominance, weight, history of prematurity and presence of comorbidities did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative groups. Rhinovirus was the most common involved pathogen, while respiratory syncytial virus (RSV) was detected in one case. SARS-CoV-2 bronchiolitis had a mild clinical course, with one patient receiving oxygen supplementation and none requiring paediatric or neonatal intensive care unit admission. Conclusions During the SARS-CoV-2 pandemic, a marked decrease in the number of bronchiolitis diagnoses and the disappearance of the RSV winter epidemic were observed. SARS-CoV-2-related bronchiolitis was rare and mostly displayed a mild clinical course.During the SARS-CoV-2 pandemic, very few infants with SARS-CoV-2 had bronchiolitis and mostly displayed a mild clinical course. Overall there was a marked decrease in bronchiolitis cases, indeed the RSV winter epidemic did not occur