Transition metal-catalysed generation and application of dihydroaromatic compounds for the synthesis of dibenzoazepine derivatives and polysubstituted benzenes

The objectives of this investigation were the development of a cobalt(I)-catalysed Diels-Alder reaction on nitrogen functionalised alkynes and the synthesis of dibenzoazepine derivatives. Starting from the discovery that the phthalimido group is a suitable protecting group for the reaction of propargylic amines with 1,3-dienes several modifications were tested and sulfimides and amides proved to be effective, although the yields were moderate. When aryl propargylic amines, synthesised via Sonogashira coupling, were tested the desired Diels-Alder adducts were obtained in excellent yields. The phthalimido-protected oxidised cycloadducts are valuable building blocks for the synthesis of polycyclic polyfunctionalised heterocyclic compounds. Alternatively, the dihydroaromatic compounds can be used as substrates for rhodium(II)-catalysed C-H activation reaction with a variety of diazo compounds as carbenoid precursors. A copper-catalysed C-H activation reaction was also developed and, although limited to stabilised carbenes, the yields were comparable with the rhodium(II)-catalysed reaction

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk

Transition metal-catalysed generation and application of dihydroaromatic compounds for the synthesis of dibenzoazepine derivatives and polysubstituted benzenes

The objectives of this investigation were the development of a cobalt(I)-catalysed Diels-Alder reaction on nitrogen functionalised alkynes and the synthesis of dibenzoazepine derivatives. Starting from the discovery that the phthalimido group is a suitable protecting group for the reaction of propargylic amines with 1,3-dienes several modifications were tested and sulfimides and amides proved to be effective, although the yields were moderate. When aryl propargylic amines, synthesised via Sonogashira coupling, were tested the desired Diels-Alder adducts were obtained in excellent yields. The phthalimido-protected oxidised cycloadducts are valuable building blocks for the synthesis of polycyclic polyfunctionalised heterocyclic compounds. Alternatively, the dihydroaromatic compounds can be used as substrates for rhodium(II)-catalysed C-H activation reaction with a variety of diazo compounds as carbenoid precursors. A copper-catalysed C-H activation reaction was also developed and, although limited to stabilised carbenes, the yields were comparable with the rhodium(II)-catalysed reaction

Behavioural and Cognitive-Behavioural Treatments of Parasomnias

Parasomnias are unpleasant or undesirable behaviours or experiences that occur predominantly during or within close proximity to sleep. Pharmacological treatments of parasomnias are available, but their efficacy is established only for few disorders. Furthermore, most of these disorders tend spontaneously to remit with development. Nonpharmacological treatments therefore represent valid therapeutic choices. This paper reviews behavioural and cognitive-behavioural managements employed for parasomnias. Referring to the ICSD-3 nosology we consider, respectively, NREM parasomnias, REM parasomnias, and other parasomnias. Although the efficacy of some of these treatments is proved, in other cases their clinical evidence cannot be provided because of the small size of the samples. Due to the rarity of some parasomnias, further multicentric researches are needed in order to offer a more complete account of behavioural and cognitive-behavioural treatments efficacy

DROSHA is recruited to DNA damage sites by the MRN complex to promote non-homologous end joining

The DNA damage response (DDR) is the signaling cascade that recognizes DNA double-strand breaks (DSBs) and promotes their resolution via the DNA repair pathways of non-homologous end joining (NHEJ) or homologous recombination (HR). We and others have shown that DDR activation requires DROSHA; however, whether DROSHA exerts its functions by associating with damage sites, what controls its recruitment, and how DROSHA influences DNA repair remains poorly understood. Here, we show that DROSHA associates with DSBs independently of transcription. Neither H2AX, nor ATM or DNA-PK kinase activities are required for recruitment of DROSHA to break sites. Rather, DROSHA interacts with RAD50, and inhibition of the MRN complex by mirin treatment abolishes this interaction. MRN complex inactivation by RAD50 knockdown or mirin treatment prevents DROSHA recruitment to DSBs and, as a consequence, also prevents 53BP1 (also known as TP53BP1) recruitment. During DNA repair, DROSHA inactivation reduces NHEJ and boosts HR frequency. Indeed, DROSHA knockdown also increases the association of downstream HR factors such as RAD51 to DNA ends. Overall, our results demonstrate that DROSHA is recruited at DSBs by the MRN complex and directs DNA repair towards NHEJ

Outcome at three months of COPD patients with acute hypercapnic respiratory failure treated with NPPV in an Acute Medicine Ward

Non invasive positive pressure ventilation (NPPV) is increasingly used for patients with hypercapnic respiratory failure secondary to acute exacerbation of chronic obstructive pulmonary disease (COPD). NPPV has been shown to improve arterial blood gas tensions and dyspnoea and to prevent the need for intubation in patients admitted to hospital with an exacerbation of COPD associated with respiratory acidosis. Although advantages of NPPV over conventional treatment have been convincingly documented in the short period, there are fewer data as to the outcomes following hospital discharge. We have undertaken a prospective descriptive study to obtain comprehensive data on the in hospital and 3 month outcomes of a cohort of 57 COPD patients treated with NPPV for acute hypercapnic respiratory failure as a first intervention in addition to usual medical care. Patients with a COPD exacerbation had better outcomes than patients with COPD complicated by other acute conditions. Pneumonia was specifically associated with a higher inhospital risk of death. In our series about one in four patients with an indicator of previous severe respiratory disease (past admission for acute respiratory failure, previous use of NPPV, long term oxygen therapy or home NPPV) was dead at three months after discharge and almost one in two was dead or had been readmitted. On the contrary, patients without indicators of previous severe respiratory disease benefited from NPPV during an acute episode of respiratory failure and had a chance of approximately 80% of being alive and free from recurrence at three months

Highly diastereoselective cyanation of methyl ketimines obtained from (R)-glyceraldehyde

Addition of trimethylsilyl cyanide to ketimines derived from (R)-2,2-dimethyl-1,3-dioxolan-4-yl methyl ketone to generate a quaternary stereocenter has been achieved with high yields and excellent diastereoselectivity. The stereoselectivity was found to be temperature and solvent dependent. The β-hydroxy-α-amino nitrile of syn configuration was the major compound in kinetically controlled reactions, whereas the anti stereoisomer was obtained in excess in thermodynamically controlled reactions. Double stereodifferentiation under kinetic control conditions was successful, and the cyanation reaction occurred with complete syn diastereoselectivity using the matched pair. The versatility of the resulting amino nitrile as a synthetic intermediate was tested by performing the synthesis of orthogonally protected (R)-(2-aminomethyl)alanine.This work was supported by the Spanish MCYT and FEDER (Project CTQ2004-05358) and the Diputación General de Aragón. R.D. was supported by a Spanish MCYT Predoctoral Fellowship.Peer reviewe

Accelerated solvent extraction by using an ‘in-line’ clean-up approach for multiresidue analysis of pesticides in organic honey

<p>The worldwide loss of honeybee colonies may be due to their exposure to several contaminants (i.e., pesticides); such contamination may also have impacts on consumers’ health. Therefore, it is essential to develop quick and new methods to detect several pesticide residues in honey samples. In this study, the effectiveness of accelerated solvent extraction (ASE) was compared with QuEChERS methods for the analysis of 53 pesticides in organic honey by gas chromatography-triple quadrupole mass spectrometry. Two simple and rapid ASE methods with ‘in-line’ clean-up were optimised and then compared with QuEChERS. Hexane–ethyl acetate (Hex:EtAc) and Florisil were chosen as extraction solvent and retainer for the first ASE method respectively; acetonitrile and a primary–secondary amine phase (ACN-PSA) were selected for the second ASE method. The methods were validated according to the European Union SANTE/11945/2015 guidelines. The validation parameters showed that QuEChERS and ASE with PSA as retainer had better repeatability than ASE with Hex:EtAc and Florisil. In particular, QuEChERS and ASE (ACN-PSA) showed good recovery, according to the SANTE criteria, for the majority of investigated pesticides. Conversely, when ASE with Hex:EtAc and Florisil was used as the retainer, several compounds showed recoveries lower than the acceptable value of 70%. The ASE in-line method was finally applied to evaluate pesticide concentration in organic honey samples.</p

MRE11-RAD50-NBS1 Complex Is Sufficient to Promote Transcription by RNA Polymerase II at Double-Strand Breaks by Melting DNA Ends

The MRE11-RAD50-NBS1 (MRN) complex supports the synthesis of damage-induced long non-coding RNA (dilncRNA) by RNA polymerase II (RNAPII) from DNA double-strand breaks (DSBs) by an unknown mechanism. Here, we show that recombinant human MRN and native RNAPII are sufficient to reconstitute a minimal functional transcriptional apparatus at DSBs. MRN recruits and stabilizes RNAPII at DSBs. Unexpectedly, transcription is promoted independently from MRN nuclease activities. Rather, transcription depends on the ability of MRN to melt DNA ends, as shown by the use of MRN mutants and specific allosteric inhibitors. Single-molecule FRET assays with wild-type and mutant MRN show a tight correlation between the ability to melt DNA ends and to promote transcription. The addition of RPA enhances MRN-mediated transcription, and unpaired DNA ends allow MRN-independent transcription by RNAPII. These results support a model in which MRN generates single-strand DNA ends that favor the initiation of transcription by RNAPII.ISSN:2666-3864ISSN:2211-124

MUSE Analysis of Gas around Galaxies (MAGG) – IV. The gaseous environment of z ∼ 3–4 Ly α emitting galaxies

We study the link between galaxies and H I-selected absorption systems at z ∼ 3–4 in the MUSE Analysis of Gas around Galaxies (MAGG) survey, an ESO large programme consisting of integral field spectroscopic observations of 28 quasar fields hosting 61 strong absorbers with NH I 1016.5 cm−2. We identify 127 Ly α emitting galaxies (LAEs) around the absorbers, corresponding to a detection rate of 82 ± 16 per cent. The luminosity function of these LAEs is ≈5 times higher in normalization than the field population and we detect a significant clustering of galaxies with respect to the gas, confirming that high column density absorbers and LAEs trace each other. Between 30 and 40 per cent of the absorbers are associated with multiple LAEs, which lie preferentially along filaments. Galaxies in groups also exhibit a three times higher covering factor of optically thick gas compared to isolated systems. No significant correlations are identified between the emission properties of LAEs and the absorption properties of optically thick gas clouds, except for a weak preference of brighter and multiple galaxies to reside near broad absorbers. Based on the measured impact parameters and the covering factor, we conclude that the near totality of optically thick gas in the Universe can be found in the outer circumgalactic medium (CGM) of LAEs or in the intergalactic medium (IGM) in proximity to these galaxies. Thus, LAEs act as tracers of larger scale structures within which both galaxies and optically thick clouds are embedded. The patchy and inhomogeneous nature of the CGM and IGM explains the lack of correlations between absorption and emission properties. This implies that very large samples are needed to unveil the trends that encode the properties of the baryon cycle