Asymmetric Synthesis of Cyclohexene Nucleoside Analogues

The asymmetric synthesis of novel cyclohexene nucleoside analogues 12 and 15 is described. An enantiospecific DielsAlder reaction between (E,E)-diene 2 and (+)-5-(D-mentyloxy)-2(5H)- furanone 3 provided the cycloadduct isomer 4. Three additional steps yielded amine 8 allowing the constructions of the thymine and adenine moieties to afford intermediates 11 and 14, respectively. Amination or cyclization and removal of the protecting groups occurred in one step in the presence of ammonia, giving the target six-membered ring nucleosides

A modified vimentin histological score helps recognize pulmonary sarcomatoid carcinoma in small biopsy samples

Background: As pulmonary sarcomatoid carcinomas (PSCs) are life-threatening tumors, an improvement in their recognition in small-sized tumor samples is clinically warranted. Materials and Methods: Preoperative biopsy samples and paired surgical specimens from 20 pleomorphic carcinomas, two pulmonary blastomas and one carcinosarcoma (training set) were studied for vimentin immunohistochemistry. A modified vimentin histologic score (M-VHS) was devised by multiplying three independently assessed parameters, i.e. the percentage of positive cells (from 0 to 5+, by quintiles), the intensity of immunostaining (low=1 vs. strong=2) and the distribution pattern within the cytoplasm (partial=1 vs. diffuse=2), so ranging from 0 to 20. Forty-eight consecutive and independent cases of non-small cell lung carcinoma (NSCLC), including two additional cases of PSC, were used as control groups (validation set). Results: No differences in M-VHS were found between biopsies and surgical specimens of PSC, thus confirming the occurrence of stable epithelial mesenchymal transition (EMT) and hence the specific diagnosis of PSC. All types of PSC shared the same M-VHS. The M-VHS of 46 conventional NSCLC was by far lower (p<0.0001), whereas two additional cases of PSC showed the same results as the training set. Poorly differentiated NSCLC with marked pleomorphism but not stable EMT did not exhibit significantly increased M-VHS values. Conclusion: M-VHS helped in morphological analysis to render more definite diagnoses on small biopsies of PSC

Long-term outcomes of a pilot CT screening for lung cancer

Background: Low-dose computed tomography (CT) screening can detect early stage lung cancer in high-risk populations. However, no data on repeated annual screening over more than 5 years are available, and the impact of screening on lung cancer mortality is controversial. Methods: We analysed outcomes in high-risk asymptomatic volunteers (smokers and former smokers, >50 years) enrolled in a pilot study over 1 year from June 2000, who received annual low-dose CT for 7 years. Cumulative lung cancer incidence and survival were represented by Kaplan 12Meier curves. Standardized incidence and mortality ratios were used to estimate risks relative to the general Italian and US population. Results: Compliance was 86% at the end of the seventh year in 1035 recruited volunteers (71% men, mean age 58 years). Lung cancer was diagnosed in 54 (5.3%); radical surgery was possible in 48/54 (87%); 39/54 (72%) had stage I disease. Five-year survival was 63% overall, 89% for stage I cases. During 6308 person-years of observation, 47 participants had died versus 75 expected in the Italian general population standardised for age and sex. Fourteen lung cancer deaths were registered versus 27 expected in a standardised US smoker population. Conclusions: Seventy percent of screening-diagnosed patients had stage I disease, and the survival of screen-detected cancer patients was high. Lung cancer mortality was favourable compared to age- and sex-matched population of US smokers, suggesting that mortality can be lowered by screening, although larger trials with longer follow-up are necessary to confirm these findings

Stationary distributions for diffusions with inert drift

Consider reflecting Brownian motion in a bounded domain in $${\mathbb R^d}$$ that acquires drift in proportion to the amount of local time spent on the boundary of the domain. We show that the stationary distribution for the joint law of the position of the reflecting Brownian motion and the value of the drift vector has a product form. Moreover, the first component is uniformly distributed on the domain, and the second component has a Gaussian distribution. We also consider more general reflecting diffusions with inert drift as well as processes where the drift is given in terms of the gradient of a potential

Wet deposition in the remote western and central Mediterranean as a source of trace metals to surface seawater

Abstract. This study reports the only recent characterization of two contrasted wet deposition events collected during the PEACETIME (ProcEss studies at the Air–sEa Interface after dust deposition in the MEditerranean Sea) cruise in the open Mediterranean Sea (Med Sea) and their impact on trace metal (TM) marine stocks. Rain samples were analysed for Al, 12 TMs (Co, Cd, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Ti, V and Zn) and nutrient (N, P, dissolved organic carbon) concentrations. The first rain sample collected in the Ionian Sea (Rain ION) was a typical regional background wet deposition event, whereas the second rain sample collected in the Algerian Basin (Rain FAST) was a Saharan dust wet deposition event. Even in the remote Med Sea, all background TM inputs presented an anthropogenic signature, except for Fe, Mn and Ti. The concentrations of TMs in the two rain samples were significantly lower compared to concentrations in rains collected at coastal sites reported in the literature, due to the decrease in anthropogenic emissions during the preceding decades. The atmospheric TM inputs were mainly dissolved forms, even in dusty Rain FAST. The TM stocks in the mixed layer (ML, 0–20 m) at the FAST station before and after the event showed that the atmospheric inputs were a significant supply of particulate TMs and dissolved Fe and Co for surface seawater. Even if the wet deposition delivers TMs mainly in soluble form, the post-deposition aerosol dissolution could to be a key additional pathway in the supply of dissolved TMs. At the scale of the western and central Mediterranean, the atmospheric inputs were of the same order of magnitude as ML stocks for dissolved Fe, Co and Zn, highlighting the role of the atmosphere in their biogeochemical cycles in the stratified Med Sea. In case of intense dust-rich wet deposition events, the role of atmospheric inputs as an external source was extended to dissolved Co, Fe, Mn, Pb and Zn. Our results suggest that the wet deposition constitutes only a source of some of dissolved TMs for Med Sea surface waters. The contribution of dry deposition to the atmospheric TM inputs needs to be investigated.</jats:p

Mortality risk according to different clinical characteristics of first episode of liver decompensation in cirrhotic patients: a nationwide, prospective, 3-year follow-up study in Italy.

OBJECTIVES: The occurrence of decompensation marks a crucial turning point in the course of cirrhosis. The purpose of this study was to assess the risk of mortality according to the clinical characteristics of first decompensation, considering also the impact of acute-on-chronic liver failure (AoCLF). METHODS: We conducted a prospective nationwide inception cohort study in Italy. Decompensation was defined by the presence of ascites, either overt or detected by ultrasonography (UD), gastroesophageal variceal bleeding (GEVB), and hepatic encephalopathy (HE). AoCLF was defined according to the Asian Pacific Association for the Study of the Liver criteria. Multivariable Cox proportional hazards regression was used to analyze the risk of failure (death or orthotopic liver transplantation (OLT)). RESULTS: A total of 490 consecutive cirrhotic patients (314 males, mean age 60.9±12.6 years) fulfilled the study criteria. AoCLF was identified in 59 patients (12.0%). Among the remaining 431 patients, ascites were found in 330 patients (76.6%): in 257 (77.8%) as overt ascites and in 73 (22.2%) as UD ascites. GEVB was observed in 77 patients (17.9%) and HE in 30 patients (7.0%). After a median follow-up of 33 months, 24 patients underwent OLT and 125 died. The cumulative incidence of failure (death or OLT) after 1, 2, and 3 years was, respectively, 28, 53, and 62% in patients with AoCLF; 10, 18, and 25% in patients with UD ascites; 17, 31, and 41% in patients with overt ascites; and 8, 12, and 24% in patients with GEVB (P<0.0001). CONCLUSIONS: AoCLF is responsible for a relevant proportion of first decompensation in cirrhotic patients and is associated with the poorest outcome. Patients with UD ascites do not have a negligible mortality rate and require clinical monitoring similar to that of patients with overt ascites

Designing citizen science tools for learning: lessons learnt from the iterative development of nQuire

This paper reports on a 4-year research and development case study about the design of citizen science tools for inquiry learning. It details the process of iterative pedagogy-led design and evaluation of the nQuire toolkit, a set of web-based and mobile tools scaffolding the creation of online citizen science investigations. The design involved an expert review of inquiry learning and citizen science, combined with user experience studies involving more than 200 users. These have informed a concept that we have termed ‘citizen inquiry’, which engages members of the public alongside scientists in setting up, running, managing or contributing to citizen science projects with a main aim of learning about the scientific method through doing science by interaction with others. A design-based research (DBR) methodology was adopted for the iterative design and evaluation of citizen science tools. DBR was focused on the refinement of a central concept, ‘citizen inquiry’, by exploring how it can be instantiated in educational technologies and interventions. The empirical evaluation and iteration of technologies involved three design experiments with end users, user interviews, and insights from pedagogy and user experience experts. Evidence from the iterative development of nQuire led to the production of a set of interaction design principles that aim to guide the development of online, learning-centred, citizen science projects. Eight design guidelines are proposed: users as producers of knowledge, topics before tools, mobile affordances, scaffolds to the process of scientific inquiry, learning by doing as key message, being part of a community as key message, every visit brings a reward, and value users and their time

Reversible Light-Induced Dimerization of Secondary Face Azobenzene-Functionalized β-Cyclodextrin Derivatives

β-cyclodextrin (βCyD) derivatives equipped with aromatic appendages at the secondary face exhibit tailorable self-assembling capabilities. The aromatic modules can participate in inclusion phenomena and/or aromatic-aromatic interactions. Supramolecular species can thus form that, at their turn, can engage in further co-assembling with third components in a highly regulated manner; the design of nonviral gene delivery systems is an illustrative example. Endowing such systems with stimuli responsiveness while keeping diastereomeric purity and a low synthetic effort is a highly wanted advancement. Here, we show that an azobenzene moiety can be “clicked” to a single secondary O-2 position of βCyD affording 1,2,3-triazole-linked βCyD-azobenzene derivatives that undergo reversible light-controlled self-organization into dimers where the monomer components face their secondary rims. Their photoswitching and supramolecular properties have been thoroughly characterized by UV-vis absorption, induced circular dichroism, nuclear magnetic resonance, and computational techniques. As model processes, the formation of inclusion complexes between a water-soluble triazolylazobenzene derivative and βCyD as well as the assembly of native βCyD/βCyD-azobenzene derivative heterodimers have been investigated in parallel. The stability of the host-guest supramolecules has been challenged against the competitor guest adamantylamine and the decrease of the medium polarity using methanol-water mixtures. The collective data support that the E-configured βCyD-azobenzene derivatives, in aqueous solution, form dimers stabilized by the interplay of aromatic-aromatic and aromatic-βCyD cavity interactions after partial reciprocal inclusion. Photoswitching to the Z-isomer disrupts the dimers into monomeric species, offering opportunity for the spatiotemporal control of the organizational status by light.Ministerio de Ciencia e Innovación PID2019-105858RB-I00, PID2020-118403GB-I00, PID2020-118384GB-I00, PID2020-119130GB-I00Fondo Europeo de Desarrollo Regional PID2021-124247OB-C21Junta de Andalucía P20_00166, US-1380698, P12-FQM-1467Universidad de Sevilla FPU18/02922, FPU19/0436