SINTESI DI BIOISOSTERI DEGLI OLIGOMANNOSI CON POTENZIALE ATTIVITA’ ANTITUBERCOLARE

Mycobacterium tuberculosis is the cause of the deadly infectious disease, tuberculosis (TB). According to the World Health Organization, nearly one–third of the world's population has been exposed to the tuberculosis pathogen and nearly 1.6 million deaths result every year. TB is, in addition, the leading infectious killer of people living with HIV/AIDS. Recent outbreaks of drug-resistant TB in many industrialized nations have led to a new interest in the disease, and basic research and drug development have again become priorities. The Mycobacterium organism possesses a complex cell wall including glycophospholipids such as phosphatidylinositiol mannosides (PIMs), lipomannan (LM), and lipoarabinomannan (LAM). These glycolipids all contain a common α-1,6-linked mannoside core, and the higher PIMs and LAM possess α-1,2-linked mannosyl residues. It has been shown that simple α-1,6-linked oligomannosides can act as substrates for α-1,6- mannosyltransferases in mycobacterium, i.e. the enzymes that promote the synthesis of the above mentioned PIMs, LM, and LAM This thesis focused on synthesis of potential inhibitors of α-1,6-mannosyltransferases . Iterative and/or a convergent approaches to (1,6)-oligomannoside mimics are reported. These synthetic oligosaccharides display the 1,2,3-triazole ring as a rigid and stable linker between α-D-mannose residues (triazolo-oligomannoses). Moreover the 6-position of the terminal mannosyl residue is deoxygenated. This structural feature is expected to prevent such compounds from acting as substrates for α-1,6-mannosyltransferases in mycobacterium. High stability can be foreseen for these oligomers owing to the resistance of anomeric carboncarbon bond and triazole ring toward chemical and enzymatic degradation. The assembly of the designed triazolo-oligomannoses relied on the great efficiency of the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition of suitable building blocks duly prepared for his purpose. In this way six triazole-linked oligomannosides with progressive length chain (2-16 mannose units) were prepared in order to evaluate the influence of length on their affinity toward the α-1,6-mannosyltransferases. In vitro assays showed that the hexamannoside and octamannoside were the most active derivatives (95% inhibition at 1 mM concentration) and it was therefore deduced that these compounds were endowed with the optimal chain length for the interaction with α-1,6-mannosyltransferases

Transferability Of Mesohabitat Suitability Criteria In Northern Italy

In the framework of water resources planning and management, the MesoHABSIM (MesoHABitat SImulation Model) approach demonstrated high potential to assess suitable environmental conditions for freshwater fish species. In the present study, the transferability capabilities of mesohabitat suitability criteria were evaluated in nine streams across Northern Italy. In particular, the Random Forest (RF) technique was used to calibrate and validate suitability criteria for adult and juvenile life stages of brown trout (Salmo trutta), marble trout (Salmo marmoratus), bullhead (Cottus gobio) Italian barbel (Barbus plebejus), and Italian vairone (Telestes muticellus). Presence/absence binary models were calibrated at the mesohabitat scale (i.e., the geomorphic unit scale) using field data collected in reference sites, selected for their natural hydro-morphological conditions and habitat characteristics. Model transferability tests were performed in streams located in different regions within the distribution area of the fish and not included in the model calibration dataset. Predictive capacities of the models were very good in terms of accuracy (ranging from 75% to 82%) and true skill statistic (ranging from 52% to 75%). The high predictive performances can be related to (i) the use of an ecologically relevant spatial resolution (mesohabitat) to predict fish presence, (ii) a robust and adequate hydro-morphological characterization of the analyzed geomorphic units, and (iii) the large number of mesohabitat descriptors provided by the MesoHABSIM approach. Results showed that mesohabitat suitability criteria based on RF can be considered transferable among streams located in different regions of Northern Italy, especially when river channels are characterized by similar hydro-morphological characteristics

Translational approach to address therapy in myotonia permanens due to a new SCN4A mutation

Objective: We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype. Methods: Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp. Results: The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition. Conclusions: Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual

Exhaustive glycosylation, pegylation, and glutathionylation of a [G4]‐ene_(48) dendrimer via photoinduced thiol‐ene coupling

The use of free‐radical thiol‐ene coupling (TEC) for the introduction of carbohydrate, poly(ethylene glycol), and peptide fragments at the periphery of an alkene functional dendrimer has been reported in this article. Four different sugar thiols including glucose, mannose, lactose, and sialic acid, two PEGylated thiols, and the natural tripeptide glutathione were reacted with a fourth generation alkene functional dendrimer [G4]‐ene48 on irradiation at λmax 365 nm. In all cases, the 1H NMR spectra of the crude reaction mixture revealed the complete disappearance of alkene proton signals indicating the quantitative conversion of all 48 alkene groups of the dendrimer. With one exception only, all dendrimer conjugates were isolated in high yields (70–94%), validating the high efficiency of multiple TEC reactions on a single substrate. All isolated and purified compounds were analyzed by matrix assisted laser desorption ionization‐time of flight (MALDI‐TOF) spectrometry and gave spectra consistent with the assigned structure

Geohazard features of the north-western Sicily and Pantelleria

9 pages, 3 figures, supplemental material https://doi.org/10.1080/17445647.2024.2342931.-- Data availability statement: Department of Earth and Marine Science of the University of Palermo for institutional purposes, so their access will be available by contacting the reference people (attilio.sulliunipa.it) upon reasonable requestWe present maps of geohazard features identified across north-western Sicily and Pantelleria in the framework of the Magic project (MArine Geohazard along Italian Coasts), which involved Italian marine geological researchers in 2007-2013. These seafloor features were recognized using high-resolution bathymetry data and rely on the morphological expression of the seafloor and shallow sub-surface processes. The north-western Sicily is a complex continental margin, affected by morphodynamic, depositional, and tectonic processes. The Egadi offshore is controlled by fault escarpments and alternating retreating and progradational processes. Ustica and Pantelleria submerged edifices show the effect of volcanic activity. The Ustica seafloor is interested in volcanic, tectonic, and gravitational instability processes, while the Pantelleria offshore underwent erosive-depositional processes and the effect of bottom currents. Two levels of interpretation are represented: the physiographic domain at a scale of 1:250.000 and the morphological units and morpho-bathymetric elements at a 1:100.000 scaleThe Magic Project has been funded by the Italian Civil Protection Department. [...] With the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)Peer reviewe

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon