Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides

Phosphorothioates (PS) have proven their effectiveness in the area of therapeutic oligonucleotides with applications spanning from cancer treatment to neurodegenerative disorders. Initially, PS substitution was introduced for the antisense oligonucleotides (PS ASOs) because it confers an increased nuclease resistance meanwhile ameliorates cellular uptake and in-vivo bioavailability. Thus, PS oligonucleotides have been elevated to a fundamental asset in the realm of gene silencing therapeutic methodologies. But, despite their wide use, little is known on the possibly different structural changes PS-substitutions may provoke in DNA·RNA hybrids. Additionally, scarce information and significant controversy exists on the role of phosphorothioate chirality in modulating PS properties. Here, through comprehensive computational investigations and experimental measurements, we shed light on the impact of PS chirality in DNA-based antisense oligonucleotides; how the different phosphorothioate diastereomers impact DNA topology, stability and flexibility to ultimately disclose pro-Sp S and pro-Rp S roles at the catalytic core of DNA Exonuclease and Human Ribonuclease H; two major obstacles in ASOs-based therapies. Altogether, our results provide full-atom and mechanistic insights on the structural aberrations PS-substitutions provoke and explain the origin of nuclease resistance PS-linkages confer to DNA·RNA hybrids; crucial information to improve current ASOs-based therapies.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research

Biodiversity of Indigenous Saccharomyces Populations from Old Wineries of South-Eastern Sicily (Italy): Preservation and Economic Potential

In recent years, the preservation of biodiversity has become an important issue. Despite much public discussion, however, current practices in the food industry seldom take account of its potential economic importance: on the contrary, the introduction of industrialized agriculture practices over large areas has often resulted in a dramatic reduction in biodiversity

Three-row versus two-row circular staplers for left-sided colorectal anastomosis: a propensity score-matched analysis of the iCral 2 and 3 prospective cohorts

Background: Since most anastomoses after left-sided colorectal resections are performed with a circular stapler, any technological change in stapling devices may influence the incidence of anastomotic adverse events. The aim of the present study was to analyze the effect of a three-row circular stapler on anastomotic leakage and related morbidity after left-sided colorectal resections. Materials and methods: A circular stapled anastomosis was performed in 4255 (50.9%) out of 8359 patients enrolled in two prospective multicenter studies in Italy, and, after exclusion criteria to reduce heterogeneity, 2799 (65.8%) cases were retrospectively analyzed through a 1:1 propensity score-matching model including 20 covariates relative to patient characteristics, to surgery and to perioperative management. Two well-balanced groups of 425 patients each were obtained: group (A) – true population of interest, anastomosis performed with a three-row circular stapler; group (B) – control population, anastomosis performed with a two-row circular stapler. The target of inferences was the average treatment effect in the treated (ATT). The primary endpoints were overall and major anastomotic leakage and overall anastomotic bleeding; the secondary endpoints were overall and major morbidity and mortality rates. The results of multiple logistic regression analyses for the outcomes, including the 20 covariates selected for matching, were presented as odds ratios (OR) and 95% confidence intervals (95% CI). Results: Group A versus group B showed a significantly lower risk of overall anastomotic leakage (2.1 vs. 6.1%; OR 0.33; 95% CI 0.15–0.73; P = 0.006), major anastomotic leakage (2.1 vs. 5.2%; OR 0.39; 95% CI 0.17–0.87; P = 0.022), and major morbidity (3.5 vs. 6.6% events; OR 0.47; 95% CI 0.24–0.91; P = 0.026). Conclusion: The use of three-row circular staplers independently reduced the risk of anastomotic leakage and related morbidity after left-sided colorectal resection. Twenty-five patients were required to avoid one leakage

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease

Semiochemical strategies for sea louse control: host location cues

The development of behavioural bioassays and electrophysiological recording techniques has enabled the role of semiochemicals to be investigated for the first time in Lepeophtheirus salmonis (Kroyer). Adult male sea lice L salmonis were activated by, and attracted to, salmon-conditioned water (SCW) and SCW extract. Non-host fish odours, turbot-conditioned water (TCW) and turbot-conditioned water extract (TCW extract), elicited activation but no attraction in the lice. Solid-phase extraction techniques were developed to extract low molecular weight components of fish odours, and biological activity was shown to be confined to these. Electrophysiological activity from aesthetascs in the first antennae was found and neural responses to odours were recorded from the antennal nerves. Preliminary experiments on individual chemicals (isophorone, 1-octen-3-ol) linked to salmon revealed behavioural activation and electrophysiological responses in adult male L salmonis. Isophorone was shown to be significantly attractive to sea lice when placed in a slow-release system in a perfused tank of seawater in a choice situation. Proof of concept has been established for successfully extracting odour cues from seawater, analysing their biological activity and applying these to slow-release technologies for field trapping of lice. Future work involving linked GC-MS techniques using behaviour, electrophysiological responses, and organolepsis will establish further host location cues specific to Atlantic salmon. (C) 2002 Society of Chemical Industry

Piano strategico del Comune di Mazara del Vallo “Mazara città porta del Mediterraneo”

Il Piano strategico di Mazara del Vallo propone un articolato sistema di obiettivi di sviluppo per la città, attraverso un piano di azione la cui struttura si compone di quattro livelli interpretativi. - il primo livello è quello della vision, da intendersi come una prospettiva desiderabile per lo sviluppo della città, la proiezione futura di un’identità condivisa tra gli attori politici, sociali, economici e tecnici che hanno preso parte al processo di pianificazione strategica; - il secondo livello è quello dei temi strategici, ossia gli obiettivi generali necessari alla costruzione della prospettiva di cambiamento indicata dalla vision, e già riferibili a campi di politiche che è necessario attivare per perseguire le finalità del Piano; - i cantieri progettuali rappresentano il principale dispositivo di integrazione progettuale del Piano strategico, riferendosi a contesti fisici della città o a tematiche di sviluppo che, per la loro complessità e trasversalità rispetto ai Temi strategici, richiedono una particolare sinergia e complementarietà tra le azioni progettuali del Piano; - l’ultima componente è rappresentato dalle azioni progettuali, ovvero gli interventi puntuali e le politiche, materiali e immateriali, che sono stati identificati nel processo di pianificazione strategica come la necessaria base da cui partire per conseguire gli obiettivi del Piano. Il Piano ha trovato il suo punto di forza nell’informazione e nella promozione della partecipazione dei cittadini alla redazione. La prima fase di lavoro ha avuto l’obiettivo di comprendere i punti di forza e di debolezza della città, da cui partire per la “progettazione” di un quadro coerente di proposte e obiettivi d'azione volti alla valorizzazione delle risorse della città. In questa fase sono state avviate indagini diagnostiche a diversi livelli: urbanistico, ambientale, sociale ed economico. L’attenzione è stata posta in particolare sulle dinamiche di sviluppo della città di Mazara in riferimento al sistema urbano regionale e al sistema territoriale della Sicilia occidentale. I risultati di tale attività di analisi hanno avuto un fondamentale arricchimento con gli elementi di conoscenza derivanti dall’intensa attività di ascolto sociale e dai momenti di partecipazione pubblica programmati lungo tutto il processo di pianificazione. Infine sono seguiti incontri mirati, con gli amministratori e i principali stakeholder, per una migliore definizione delle azioni progettuali da inserire nel Piano strategico rivolte alla rete ferroviaria, al sistema portuale e al centro storico