Dynamic Kinetic Resolution of Hetero biaryl Ketones by Zinc- Catalyzed Asymmetr ic Hydrosil ylation

Adiastereo- and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile hetero- biaryl ketones is described. The DKR proceeds by zinc- catalyze dhydrosilylation of the carbonyl group ,thus leading to secondary alcohols bearing axial and central chirality .The strategy relies on the labilization of the stereogenic axis that takes place thanks to aLewis acid–base interaction between anitrogen atom in the heterocycle and the ketone carbonyl group .The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N-ligands or appealing axially chiral, bifunctional thiourea organocata- lysts.Ministerio de Ciencia e Innovación (Grants CTQ2016-76908-C2-1-P, CTQ2016-76908-C2-2-P, contract RYC-2013-12585)European FEDER FundsJunta de Andalucía (Grant 2012/FQM 10787)European Union - Marie Skłodowska-Curie (COFUND—Grant Agreement n 8 8 291780

A Dynamic Kinetic Asymmetric Heck Reaction for the Simultaneous Generation of Central and Axial Chirality

A highly diastereo- and enantioselective, scalable Pd-catalyzed dynamic kinetic asymmetric Heck reaction of heterobiaryl sulfonates with electron-rich olefins is described. The coupling of 2,3-dihydrofuran or N-boc protected 2,3-dihydropyrrole with a variety of quinoline, quinazoline, phthalazine, and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching excellent diastereo- and enantiomeric excesses when in situ formed [Pd0/DM-BINAP] was used as the catalyst, with loadings reduced down to 2 mol % in large scale reactions. The coupling of acyclic, electron-rich alkenes can also be performed using a [Pd0/Josiphos ligand] to obtain axially chiral heterobiaryl α-substituted alkenes in high yields and enantioselectivities. Products from Boc-protected 2,3-dihydropyrrole can be easily transformed into N,N ligands or appealing axially chiral, bifunctional proline-type organocatalysts. Computational studies suggest that a β-hydride elimination is the stereocontrolling step, in agreement with the observed stereochemical outcome of the reaction.Ministerio de Ciencia e Innovación (Grants CTQ2016-76908-C2-1-P; CTQ2016-76908-C2-2-P; CTQ2016-78083-P; RYC-2013-12585)European Commission (FEDER Programme)Junta de Andalucía (Grant 2012/FQM 10787)Universidad de Sevilla (Grant No. 1800511201)European Union - Marie Skłodowska-Curie (COFUND—Grant Agreement nº 291780

Metabolic Syndrome Impairs Notch Signaling and Promotes Apoptosis in Chronically Ischemic Myocardium

Objective Impaired angiogenesis is a known consequence of metabolic syndrome (MetS), however, the mechanism is not fully understood. Recent studies have shown that the Notch signaling pathway is an integral component of cardiac angiogenesis. We tested in a clinically relevant swine model the effects of MetS on Notch and apoptosis signaling in chronically ischemic myocardium. Methods Ossabaw swine were fed either a regular diet (CTL, n=8) or a high-cholesterol diet (MetS, n=8) to induce MetS. An ameroid constrictor was placed to induce chronic myocardial ischemia. Eleven weeks later, animals underwent cardiac harvest of the ischemic myocardium. Results There was down-regulation of pro-angiogenesis proteins Notch2, Notch4, Jagged2, Ang1 and ENOS in the MetS group compared to CTL. There was also up-regulation of pro-apoptosis protein Caspase8, and down-regulation of anti-angiogenesis protein pFOX03, and pro-survival proteins pP38 and HSP90 in the MetS group. Cell death was increased in the MetS group compared to CTL. Both CTL and MetS groups had similar arteriolar count and capillary density, and Notch3 and Jagged1 were both similarly concentrated in the smooth muscle wall in both groups. Conclusions MetS in chronic myocardial ischemia significantly impairs Notch signaling by down regulating Notch receptors, ligands and pro-angiogenesis proteins. MetS also increases apoptosis signaling, decreases survival signaling and increases cell death in chronically ischemic myocardium. Although short-term angiogenesis appears unaffected in this model of early MetS, the molecular signals for angiogenesis are impaired, thus suggesting that inhibition of Notch signaling may underlie decreased angiogenesis in later stages of MetS

The Molecular Biology of Vestibular Schwannomas and Its Association with Hearing Loss: A Review

Hearing loss is the most common symptom in patients with vestibular schwannoma (VS). In the past, compressive mechanisms caused by the tumoral mass and its growth have been regarded as the most likely causes of the hearing loss associated with VS. Interestingly, new evidence proposes molecular mechanisms as an explanation for such hearing loss. Among the molecular mechanisms proposed are methylation of TP73, negative expression of cyclin D1, expression of B7-H1, increased expression of the platelet-derived growth factor A, underexpression of PEX5L, RAD54B, and PSMAL, and overexpression of CEA. Many molecular mechanisms are involved in vestibular schwannoma development; we review some of these mechanisms with special emphasis on hearing loss associated with vestibular schwannoma

Asymmetric organocatalytic synthesis of tertiary azomethyl alcohols: key intermediates towards azoxy compounds and α-hydroxy-β-amino esters

A series of peracylated glycosamine-derived thioureas have been synthesized and their behavior as bifunctional organocatalysts has been tested in the enantioselective nucleophilic addition of formaldehyde tert-butyl hydrazone to aliphatic α-keto esters for the synthesis of tertiary azomethyl alcohols. Using the 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-d-glucosamine derived 3,5-bis-(trifluoromethyl)phenyl thiourea the reaction could be accomplished with high yields (75-98%) and moderate enantioselectivities (50-64% ee). Subsequent high-yielding and racemization-free tranformations of both aromatic- and aliphatic-substituted diazene products in a one pot fashion provide a direct entry to valuable azoxy compounds and α-hydroxy-β-amino esters.Ministerio de Economía y Competitividad CTQ2016-76908-C2-1-P, CTQ2016- 76908-C2-2-P, contract RYC-2012-10014 for G. de G.European Funds FEDERJunta de Andalucía 2012/FQM 107

Impacts of European livestock production: nitrogen, sulphur, phosphorus and greenhouse gas emissions, land-use, water eutrophication and biodiversity

Livestock production systems currently occupy around 28% of the land surface of the European Union (equivalent to 65% of the agricultural land). In conjunction with other human activities, livestock production systems affect water, air and soil quality, global climate and biodiversity, altering the biogeochemical cycles of nitrogen, phosphorus and carbon. Here, we quantify the contribution of European livestock production to these major impacts. For each environmental effect, the contribution of livestock is expressed as shares of the emitted compounds and land used, as compared to the whole agricultural sector. The results show that the livestock sector contributes significantly to agricultural environmental impacts. This contribution is 78% for terrestrial biodiversity loss, 80% for soil acidification and air pollution (ammonia and nitrogen oxides emissions), 81% for global warming, and 73% for water pollution (both N and P). The agriculture sector itself is one of the major contributors to these environmental impacts, ranging between 12% for global warming and 59% for N water quality impact. Significant progress in mitigating these environmental impacts in Europe will only be possible through a combination of technological measures reducing livestock emissions, improved food choices and reduced food waste of European citizens

Acceleration of global N₂O emissions seen from two decades of atmospheric inversion

Nitrous oxide (N2O) is the third most important long-lived GHG and an important stratospheric ozone depleting substance. Agricultural practices and the use of N-fertilizers have greatly enhanced emissions of N2O. Here, we present estimates of N2O emissions determined from three global atmospheric inversion frameworks during the period 1998–2016. We find that global N2O emissions increased substantially from 2009 and at a faster rate than estimated by the IPCC emission factor approach. The regions of East Asia and South America made the largest contributions to the global increase. From the inversion-based emissions, we estimate a global emission factor of 2.3 ± 0.6%, which is significantly larger than the IPCC Tier-1 default for combined direct and indirect emissions of 1.375%. The larger emission factor and accelerating emission increase found from the inversions suggest that N2O emission may have a nonlinear response at global and regional scales with high levels of N-input

First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors

We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5-1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2-5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.The trial was sponsored by Fundación de Investigacion Biomedica del Hospital Nino Jesus (EudraCT 2008-000364-16; NCT01844661). This work was funded by grants EC11/061, EC08/00094, and EC07/90591 from Instituto de Salud Carlos III and Fondos FEDER. M.R is supported by Asociación Pablo Ugarte, Asociación NEN, and Fundación Neuroblastoma.S

Leakage of nitrous oxide emissions within the Spanish agro-food system in 1961-2009

Abstract In this paper we examine the trends of nitrous oxide (N2O) emissions of the Spanish agricultural sector related to national production and consumption in the 1961?2009 period.The comparison between production- and consumption-based emissions at the national level provides a complete overview of the actual impact resulting from the dietary choices of a given country and allows the evaluation of potential emission leakages. On average, 1.5 % of the new reactive nitrogen that enters Spain every year is emitted as N2O. Production- and consumption-based emissions have both significantly increased in the period studied and nowadays consumption-based emissions are 45 % higher than production-based emissions. A large proportion of the net N2O emissions associated with imported agricultural godos comes from countries that are not committers for the United Nations Framework Convention on Climate Change Kyoto Protocol Annex I. An increase in feed consumption is the main driver of the changes observed, leading to a arkable emission leakage in the Spanish agricultural sector. The complementary approach used here is essential to achieve an effective mitigation of Spanish greenhouse gas emissions

A global FAOSTAT reference database of cropland nutrient budgets and nutrient use efficiency (1961–2020): nitrogen, phosphorus and potassium

Nutrient budgets help to identify the excess or insufficient use of fertilizers and other nutrient sources in agriculture. They allow for the calculation of indicators, such as the nutrient balance (surplus if positive or deficit if negative) and nutrient use efficiency, that help to monitor agricultural productivity and sustainability across the world. We present a global database of country-level budget estimates for nitrogen (N), phosphorus (P) and potassium (K) on cropland. The database, disseminated in FAOSTAT, is meant to provide a global reference, synthesizing and continuously updating the state of the art on this topic. The database covers 205 countries and territories, as well as regional and global aggregates, for the period from 1961 to 2020. Results highlight the wide range in nutrient use and nutrient use efficiencies across geographic regions, nutrients, and time. The average N balance on global cropland has remained fairly steady at about 50–55 kg ha−1 yr−1 during the past 15 years, despite increasing N inputs. Regional trends, however, show recent average N surpluses that range from a low of about 10 kg N ha−1 yr−1 in Africa to more than 90 kg N ha−1 yr−1 in Asia. Encouragingly, average global cropland N use efficiency decreased from about 59 % in 1961 to a low of 43 % in 1988, but it has risen since then to a level of 55 %. Phosphorus deficits are mainly found in Africa, whereas potassium deficits occur in Africa and the Americas. This study introduces improvements over previous work in relation to the key nutrient coefficients affecting nutrient budgets and nutrient use efficiency estimates, especially with respect to nutrient removal in crop products, manure nutrient content, atmospheric deposition and crop biological N fixation rates. We conclude by discussing future research directions and highlighting the need to align statistical definitions across research groups as well as to further refine plant and livestock coefficients and expand estimates to all agricultural land, including nutrient flows in meadows and pastures. Further information is available from https://doi.org/10.5061/dryad.hx3ffbgkh (Ludemann et al., 2023b) as well as the FAOSTAT database (https://www.fao.org/faostat/en/#data/ESB; FAO, 2022a) and is updated annually.</p