Substrate-Mediated Deactivation of a Ru(P\u3csup\u3et\u3c/sup\u3e\u3csup\u3eBu\u3c/sup\u3e2N\u3csup\u3eBn\u3c/sup\u3e2) Cooperative Complex

Ligand design for metal-ligand cooperative (MLC) catalysis is inherently more complex than that for traditional non-cooperative ligands. The basicity, sterics and structure of the acid/base group in MLC proton-transfer (PT) complexes, for instance, undoubtedly influence catalyst performance. Herein, we evaluate the highly tunable PR2NR′2 (1,5-R′-3,7-R-1,5-diaza-3,7-diphosphacyclooctane) ligand family for the first time in an organic transformation. With [Ru(Cp)(PtBu2NBn2)(MeCN)][PF6] as the catalyst, no turnover was observed in the anti-Markovnikov hydration of alkynes, a known PT MLC reaction. Treatment of the cooperative complex with phenylacetylene affords a vinylammonium product in which the pendant nitrogen atom of the PtBu2NBn2 ligand forms a Lewis acid-base adduct with the alpha-carbon atom of the vinylidene intermediate. Characterization by X-ray crystallography and NMR spectroscopy conclusively assign this structure in both the solid and the solution state. The adduct formation is irreversible, and the adduct is characterized as a catalyst deactivation product. Snapping Shut: The PR2NR′2 ligand family (R and R′ are removed for clarity in the graphic) open the door for easily tuned catalysts for cooperative organic transformations. However, the ligand swings toward the vinylidene, forming a stable (and catalytically inactive) Lewis acid-base adduct. (□ = open coordination site

Selective Oxygen Atom Insertion into an Aryl-Palladium Bond

The chemistry of a palladium(II) complex containing both an alkyl- and an aryl-palladium bond is reported. The reaction of [Pd(CH2CMe2C6H4)(MesN=CHCH=NMes)] with bromine or iodine leads to reductive elimination of 1,1-dimethylcyclobutabenzene with formation of [PdX2(MesN=CHCH=NMes)] (X = Br, I). However, the reaction with hydrogen peroxide gives [Pd(CH2CMe2C6H4O)(MesN=CHCH=NMes)] by overall oxygen atom insertion into the aryl-palladium rather than the alkyl-palladium bond. This complex [Pd(CH2CMe2C6H4O)(MesN=CHCH=NMes)] reacts with bromine, iodine, or hydrogen peroxide to give 3,3-dimethyl-2,3-dihydrobenzofuran and the corresponding complex [PdX2(MesN=CHCH=NMes)]. The mechanisms of reaction and basis for selectivity are discussed. The results support the view that oxygen atom insertion is a mechanistically viable pathway for selective catalytic oxidation of hydrocarbons by the green oxidant hydrogen peroxide

Catalytic Acceptorless Dehydrogenation of Amines with Ru(P\u3csup\u3eR\u3c/sup\u3e2N\u3csup\u3eR′\u3c/sup\u3e2) and Ru(dppp) Complexes

[Ru(Cp)(PPh2NBn2)(MeCN)]PF6 (1; PPh2NBn2 = 1,5-benzyl-3,7-phenyl-1,5-diaza-3,7-diphosphacyclooctane) and [Ru(Cp)(dppp)(MeCN)]PF6 (2; dppp = 1,3-bis(diphenylphosphino)propane) are both active toward the acceptorless dehydrogenation of benzylamine (BnNH2) and N-heterocycles. The two catalysts have similar activities but different selectivities for dehydrogenation products. Independent synthesis of a [Ru(Cp)(PPh2NBn2)(NH2Bn)]PF6 adduct (3) reveals the presence of a hydrogen bond between the bound amine and the pendent base of the PPh2NBn2 ligand. Preliminary mechanistic studies reveal that the benzylamine adduct is not an on-cycle catalyst intermediate

Pincer-plus-one ligands in self-assembly with palladium(ii): a molecular square and a molecular tetrahedron

The combination of a palladium(ii) precursor with a diimine-phenol ligand and an oxidant (H2O2 or O2) under different conditions has, serendipitously, given both a molecular square and a molecular tetrahedron by self-assembly of building blocks comprising palladium(ii) centres coordinated to the oxidised forms of the ligand

Phosphine-imine and-enamido ligands for acceptorless dehydrogenation catalysis

A highly tunable phosphine-imine ligand family is introduced. Following metallation with ruthenium, deprotonation of the ligand affords a phosphine-enamido species. Complexes with the ligand in both the imine and enamido forms are active toward acceptorless dehydrogenation reactions

Aspects determining the risk of pesticides to wild bees: risk profiles for focal crops on three continents.

In order to conduct a proper risk assessment of pesticides to bees, information is needed in three areas: (i) the toxicity of the pesticide; (ii) the probability of bee exposure to that pesticide; and (iii) the population dynamics of the bee species in question. Information was collected on such factors affecting pesticide risk to (primarily wild) bees in several crops in Brazil, Kenya and The Netherlands. These data were used to construct ?risk profiles? of pesticide use for bees in the studied cropping systems. Data gaps were identified and potential risks of pesticides to bees were compared between the crops. Initially, risk profiling aims to better identify gaps in our present knowledge. In the longer term, the established risk profiles may provide structured inputs into risk assessment models for wild and managed bees, and lead to recommendations for specific risk mitigation measures.Edição dos Proceedings of the 11 International Symposium Hazards of Pesticides to Bees, Wageningen, nov. 2011

Chronic Allergic Inflammation Causes Vascular Remodeling and Pulmonary Hypertension in Bmpr2 Hypomorph and Wild-Type Mice

Loss-of-function mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene have been identified in patients with heritable pulmonary arterial hypertension (PAH); however, disease penetrance is low, suggesting additional factors play a role. Inflammation is associated with PAH and vascular remodeling, but whether allergic inflammation triggers vascular remodeling in individuals with BMPR2 mutations is unknown. Our goal was to determine if chronic allergic inflammation would induce more severe vascular remodeling and PAH in mice with reduced BMPR-II signaling. Groups of Bmpr2 hypomorph and wild-type (WT) Balb/c/Byj mice were exposed to house dust mite (HDM) allergen, intranasally for 7 or 20 weeks to generate a model of chronic inflammation. HDM exposure induced similar inflammatory cell counts in all groups compared to controls. Muscularization of pulmonary arterioles and arterial wall thickness were increased after 7 weeks HDM, more severe at 20 weeks, but similar in both groups. Right ventricular systolic pressure (RVSP) was measured by direct cardiac catheterization to assess PAH. RVSP was similarly increased in both HDM exposed groups after 20 weeks compared to controls, but not after 7 weeks. Airway hyperreactivity (AHR) to methacholine was also assessed and interestingly, at 20 weeks, was more severe in HDM exposed Bmpr2 hypomorph mice versus WT. We conclude that chronic allergic inflammation caused PAH and while the severity was mild and similar between WT and Bmpr2 hypomorph mice, AHR was enhanced with reduced BMPR-II signaling. These data suggest that vascular remodeling and PAH resulting from chronic allergic inflammation occurs independently of BMPR-II pathway alterations

Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial

Background: S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke. Methods: RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18–85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7–20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0–1 versus 2–6 and 0–2 versus 3–6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov, NCT02877615. Findings: Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64–1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81–1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0–2 vs 3–6 or mRS 0–1 vs 2–6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2–8] in 150 mg S44819 group, 4 [2–7] in 300 mg S44819 group, and 4 [2–6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0–26·0] in 150 mg S44819 group, 23·0 [19·0–26·5] in 300 mg S44819 group, and 22·0 [17·0–26·0] in placebo group), time needed to complete parts A (50 s [IQR 42–68] in 150 mg S44819 group, 49 s [36–63] in 300 mg S44819 group, and 50 s [38–68] in placebo group) and B (107 s [81–144] in 150 mg S44819 group, 121 s [76–159] in 300 mg S44819 group, and 130 s [86–175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60–100] in 150 mg S44819 group, 90 [70–100] in 300 mg S44819 group, and 90 [70–100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths. Interpretation: There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans. Funding: Servier

Agricultural policies exacerbate honeybee pollination service supply-demand mismatches across Europe

Declines in insect pollinators across Europe have raised concerns about the supply of pollination services to agriculture. Simultaneously, EU agricultural and biofuel policies have encouraged substantial growth in the cultivated area of insect pollinated crops across the continent. Using data from 41 European countries, this study demonstrates that the recommended number of honeybees required to provide crop pollination across Europe has risen 4.9 times as fast as honeybee stocks between 2005 and 2010. Consequently, honeybee stocks were insufficient to supply >90% of demands in 22 countries studied. These findings raise concerns about the capacity of many countries to cope with major losses of wild pollinators and highlight numerous critical gaps in current understanding of pollination service supplies and demands, pointing to a pressing need for further research into this issue

Characteristics and Outcomes of Patients With Cerebral Venous Sinus Thrombosis in SARS-CoV-2 Vaccine–Induced Immune Thrombotic Thrombocytopenia

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson). Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS. Design, setting, and participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination. Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria. Main outcomes and measures: Clinical characteristics and mortality rate. Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later. Conclusions and relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.info:eu-repo/semantics/publishedVersio