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Los problemas principales que se discuten en torno a la Escritura son el de la inspiración, el de los géneros literarios, y el de las relaciones entre el canon, la inspiración y el origen de la Iglesia. El presente estudio tiene por objeto revisar la problemática relativa a la inspiración bíblica.

El estudio, escrito en los primeros años 1960 e inédito hasta hoy, trata sobre la pobreza y la propiedad en la tradición jesuita. Tras una breve introducción filosófico-social y una aproximación histórico-jurídica a la cuestión de la pobreza colectiva en la Iglesia, a continuación se trata de la cuestión de los bienes eclesiásticos y exponer de la pobreza en la Compañía de Jesús, para en apartados sucesivos el pensamiento de san Ignacio y el de Francisco Suárez sobre la pobreza colectiva. Unas breves conclusiones, referidas a los primeros apartados no específicamente jesuitas, cierran el estudio. A partir de la espiritualidad y del pensamiento de san Ignacio, recogido en las Constituciones de la Compañía de Jesús y en algunas actuaciones suyas, y de la posición doctrinal de Francisco Suárez con ocasión de la fundación real del colegio jesuita de Salamanca, así como ante la tercera congregación general jesuita en 1608, el autor concluye que tanto uno como otro concebían la pobreza, y en relación con ella la propiedad, de acuerdo con la doctrina común de la Iglesia de entonces, aunque superando la tensión entre institucionalistas y funcionalistas. Para ambos, la pobreza de la Compañía de Jesús es la propia de una institución carismática en la que los bienes son concebidos sólo como instrumentos de Dios. A ese fin –el de ser meros instrumentos divinos–tienden tanto la espiritualidad ignaciana como el pensamiento suareciano.

Mesenchymal stem cells (MSC) have immune regulatory properties that may ameliorate pathophysiological processes in sepsis. We determined the effect of allogeneic adipose-derived MSCs (Cx611) on the host response during sepsis due to community-acquired bacterial pneumonia (CABP) by measuring 29 plasma biomarkers and blood transcriptomes at six time points in 82 patients randomised to two intravenous infusions of Cx611 or placebo. Cx611 treatment enhanced several endothelial cell and procoagulant response plasma biomarkers, and led to increased expression of pathways related to innate immunity, haemostasis and apoptosis. Cx611 infusion in sepsis due to CABP is associated with broad host response alterations., Competing Interests: Competing interests: DVO, KJG and EL are employed by Takeda Pharmaceuticals, which produces Cx611., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Artisanal and small-scale gold mining (ASGM) in the Amazon has degraded tropical forests and escalated mercury (Hg) pollution, affecting biodiversity, ecological processes and rural livelihoods. In the Peruvian Amazon, ASGM annually releases some 181 tons of Hg into the environment. Despite some recent advances in understanding the spatial distribution of Hg within gold mine spoils and the surrounding landscape, temporal dynamics in Hg movement are not well understood. We aimed to reveal spatio-temporal trends of soil Hg in areas degraded by ASGM.,. We analyzed soil and sediment samples during the dry and rainy seasons across 14 ha of potentially contaminated sites and natural forests, in the vicinities of the Native community of San Jacinto in Madre de Dios, Peru. Soil Hg levels of areas impacted by ASGM (0.02 ± 0.02 mg kg -1 ) were generally below soil environmental quality standards (6.60 mg kg -1 ). However, they showed high variability, mainly explained by the type of natural cover vegetation, soil organic matter (SOM), clay and sand particles. Temporal trends in Hg levels in soils between seasons differed between landscape units distinguished in the mine spoils. During the rainy season, Hg levels decreased up to 45.5% in uncovered soils, while in artificial pond sediments Hg increased by up to 961%. During the dry season, uncovered degraded soils were more prone to lose Hg than sites covered by vegetation, mainly due to higher soil temperatures and concomitantly increasing volatilization. Soils from natural forests and degraded soil covered by regenerating vegetation showed a high capacity to retain Hg mainly due to the higher plant biomass, higher SOM, and increasing concentrations of clay particles. Disturbingly, our findings suggest high Hg mobility from gold mine spoil to close by sedimentary materials, mainly in artificial ponds through alluvial deposition and pluvial lixiviation. Thus, further research is needed on monitoring, and remediation of sediments in artificial to design sustainable land use strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Oxygen atom transfer (OAT) from N 2 O to the Ni-H bond of proton-responsive picoline-derived CNP nickel complexes has been investigated both experimentally and theoretically. These Ni-CNP complexes efficiently catalyse the reduction of N 2 O with pinacolborane (HBpin) under mild conditions.

Purpose: Evaluate the safety profile of expanded allogeneic adipose-derived mesenchymal stem cell (eASC) for the treatment of severe community-acquired bacterial pneumonia (CABP)., Materials and Methods: Randomized, multicenter, double-blind, placebo-controlled, phase 1b/2a trial. Patients with severe CABP were enrolled to receive intravenous infusions of Cx611 or placebo. The primary objective was safety including hypersensitivity reactions, thromboembolic events, and immunological responses to Cx611. The secondary endpoints included the clinical cure rate, ventilation-free days, and overall survival (Day 90)., Results: Eighty-three patients were randomized and received infusions (Cx611: n = 42]; placebo: n = 41]. The mean age was similar (Cx611: 61.1 [11.2] years; placebo: 63.4 [10.4] years). The number of AEs and treatment-emergent AEs were similar (243; 184 and 2; 1) in Cx611 and placebo respectively. Hypersensitivity reactions or thromboembolic events were similar (Cx611: n = 9; placebo: n = 12). Each study arm had similar anti-HLA antibody/DSA levels at Day 90. The clinical cure rate (Cx611: 86.7%; placebo: 93.8%), mean number of ventilator-free days (Cx611: 12.2 [10.29] days; placebo: 15.4 [10.75] days), and overall survival (Cx611: 71.5%; placebo: 77.0%) did not differ between study arms., Conclusion: Cx611 was well tolerated in severe CABP. These data provide insights for future stem cell clinical study designs, endpoints and sample size calculation., Trial Registration: NCT03158727 (retrospectively registered: May 09, 2017). Full study protocol: https://clinicaltrials.gov/ProvidedDocs/27/NCT03158727/Prot_000.pdf., Competing Interests: Declaration of Competing Interest PFL has received honorarium from Takeda for blinded adjudication activities related to the SEPCELL trial and received consulting fees with Inotrem and Adrenomed. MSG has received honorarium from Takeda for blinded adjudication activities related to the SEPCELL trial. TvDP has received honorarium from Takeda for blinded adjudication activities related to the SEPCELL trial and received consulting fees from Pluristem outside the trial (both paid to Amsterdam UMC). XW was part of the clinical coordinating center located at Cliniques universitaires Saint-Luc, which assessed all patients' eligibility. FMS declares no conflict of interest. GH has received speaking fees and travel expenses from Fisher & Paykel Healthcare. RF has received consulting fees with Grifols, MSD, Pfizer, Shionogi, Gilead, Baxter, GSK, Menarini, and Boehringer outside the trial. JC has no conflict of interest. KAC and AS were salaried employees of Takeda Pharmaceuticals, Cambridge, MA, USA at the time of the study. BZ is a salaried employee of Takeda Pharmaceuticals, Cambridge, MA, USA. EL and OdlR are salaried employees of Takeda Madrid, Cell Therapy Technology Center, Tres Cantos, Spain. BF has received honorarium from Takeda for blinded adjudication activities related to the SEPCELL trial and consulting fees with Aridis, Enlivex, Inotrem, AM-Pharma, and GSK outside the trial., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The body mass index (BMI) ≥30 kg/m 2 is the universally accepted cut-off point for defining obesity; however, its accuracy in classifying obesity in older adults is poorly understood., Objectives: To assess the performance of the BMI cut-off point ≥30 kg/m 2 in classifying obesity in older adults, using the fat mass index (FMI) and fat mass percentage (FM%) as reference criteria; and to establish region- and sex-specific BMI-based cut-off points to classify obesity in older adults., Methods: The present study is a secondary analysis derived from a cross-sectional project that included a sample of 1463 older adults from ten Latin American and Caribbean countries. Volunteers underwent total body water measurements using the deuterium dilution technique to determine FMI and FM%. Accuracy of the BMI and derived cutoff points was assessed by the area under the receiver operating characteristic curve (AUC)., Results: The BMI cut-off point ≥30 kg/m 2 had low sensitivity for classifying obesity in these older adults compared to the FMI and FM%. The AUC values for the optimal BMI-derived cut-off points showed an acceptable-to-outstanding discriminatory capacity in diagnosing obesity defined by the FMI. There was also a better balance between sensitivity and specificity than with the values obtained by a BMI ≥30 kg/m 2 in older subjects in both regions., Conclusion: The BMI cut-off point ≥30 kg/m 2 had poor sensitivity for accurately diagnosing obesity in older adults from two regions. The region- and sex-specific BMI-derived cut-off points for defining obesity using the FMI are more accurate in classifying obesity in older men and women subjects from both regions., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A series of enantiopure chiral NH 2 /SO palladium complexes have been synthesised with high yields by treating the corresponding tert -butylsulfinamide/sulfoxide derivatives with Pd(CH 3 CN) 2 Cl 2 . The enantiopure chiral ligands were prepared by stereoselective addition of tert -butyl or phenyl methylsulfinyl carbanions to different tert -butylsulfinylimines. In all cases, coordination occurs with concomitant desulfinylation. X-ray studies of the Pd complexes showed a higher trans influence of the phenylsulfinyl group in comparison to that of the tert -butylsulfinyl group. Furthermore, we have obtained and characterised two possible palladium amine/sulfonyl complexes, epimers at sulfur, resulting from N -desulfinylation and coordination of palladium with both oxygens of the prochiral sulfonyl group. The catalytic activity and enantioselectivity of the new Pd(II) complexes of acetylated amine/ tert -butyl- and phenylsulfoxides in the carboxylated cyclopropanes arylation reaction has been studied, obtaining the best results with the phenylsulfoxide ligand 25(SC,SS) that produced the final arylated product in a 93 :7 enantiomeric ratio.

Evaluation of DFT calculated vibrational parameters for the IR and VCD spectra similarity of perezone (1) and dihydroperezone (2) was undertaken. Conformational sets were obtained using different search engines, and the parameters needed for spectra prediction were obtained using several combinations of commonly employed functionals and basis sets, and then weighted spectra were generated and compared with observed traces to provide infrared similarity (S IR ) and enantiomeric similarity index (ESI) values. These values evidenced a poor performance of the evaluated levels of theory that were overcome when using the individual scaling factors approach, providing 16% to 139% increases of the ESI values. The best performing level of theory was the B3LYP/DGDZVP2 with ESI values of 0.722 and 0.792 for 1 and 2. Moreover, a correlation analysis showed that the irregular DFT performance arises from rotational strength deviations, which suggests to discard conformational abundance accuracy as the main source of differences. Furthermore, a similarity guided conformational analysis showed that conformations with high ESI values prefer particular orientations of the CC bonds directly attached to the stereogenic carbon atom, with more distant dihedral angles having less influence. Additionally, folded and extended conformers appear to be equally capable to yield high individual ESI values, although abundances of folded conformers just account for 16% of the total population. Nevertheless, abundance optimization showed that a high ESI similarity value of 0.834, is possible when the population of these conformers is increased to 26%, suggesting that a larger abundance of these conformers might be present in solution., (© 2022 Wiley Periodicals LLC.)

The stereoselective addition of ethyl acetate enolate to the C═N bond of N-tert-butylsulfinylimines has been investigated in depth. A significant effect of the LHMDS amount and the N-sulfinylimine nature on the stereoselectivity of the process was observed. Conditions were found where sulfinylimines of differently substituted salicylaldehydes derivatives, ethyl acetate, and LHMDS afforded the corresponding addition products as a single diastereomer in good yields. The developed protocol was successfully applied to the first stereoselective synthesis of differently substituted 4-amino-3,4-dihydrocoumarin derivatives. Computational models confirmed the prominent role of the ortho aryl substituent in the stereoselectivity of the process. A significant and selective cytotoxic activity against Glioblastoma Multiforme (GBM) cancer line has been determined for the noncyclic hydroxy ester derivative., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Reduction of nitrous oxide (N 2 O) with H 2 to N 2 and water is an attractive process for the decomposition of this greenhouse gas to environmentally benign species. Herein, a series of iridium complexes based on proton-responsive pincer ligands ( 1 - 4 ) are shown to catalyze the hydrogenation of N 2 O under mild conditions (2 bar H 2 /N 2 O (1:1), 30 °C). Among the tested catalysts, the Ir complex 4 , based on a lutidine-derived CNP pincer ligand having nonequivalent phosphine and N-heterocyclic carbene (NHC) side donors, gave rise to the highest catalytic activity (turnover frequency (TOF) = 11.9 h -1 at 30 °C, and 16.4 h -1 at 55 °C). Insights into the reaction mechanism with 4 have been obtained through NMR spectroscopy. Thus, reaction of 4 with N 2 O in tetrahydrofuran- d 8 (THF- d 8 ) initially produces deprotonated (at the NHC arm) species 5 NHC , which readily reacts with H 2 to regenerate the trihydride complex 4 . However, prolonged exposure of 4 to N 2 O for 6 h yields the dinitrogen Ir(I) complex 7 P , having a deprotonated (at the P-arm) pincer ligand. Complex 7 P is a poor catalytic precursor in the N 2 O hydrogenation, pointing out to the formation of 7 P as a catalyst deactivation pathway. Moreover, when the reaction of 4 with N 2 O is carried out in wet THF- d 8 , formation of a new species, which has been assigned to the hydroxo species 8 , is observed. Finally, taking into account the experimental results, density functional theory (DFT) calculations were performed to get information on the catalytic cycle steps. Calculations are in agreement with 4 as the TOF-determining intermediate (TDI) and the transfer of an apical hydrido ligand to the terminal nitrogen atom of N 2 O as the TOF-determining transition state (TDTS), with very similar reaction rates for the mechanisms involving either the NHC- or the P-CH 2 pincer methylene linkers.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided., (© The Author(s) 2022. Published by Oxford University Press.)

Complexes Na 3 [Ag(NHC R ) 2 ], 2a-e and 2b'-c', where NHC R is a N-heterocyclic carbene of the 2,2'-(1H-2λ 3 ,3λ 4 -imidazole-1,3-diyl)dicarboxylate type, were prepared by treatment of compounds HL R , 1a-e and 1b'-c' (2-(1-(carboxyalkyl)-1H-imidazol-3-ium-3-yl)carboxylate), with silver oxide in the presence of aqueous sodium hydroxide. They were characterized by analytical, spectroscopic (infrared, IR, 1 H and 13 C nuclear magnetic resonance, NMR, and circular dichroism) and X-ray methods (2a). In the solid state, the anionic part of complex 2a, [Ag(NHC H ) 2 ] 3- , shows a linear disposition of C carbene -Ag-C carbene atoms and an eclipsed conformation of the two NHC ligands. The proposed bis(NHC) nature of the silver complexes was maintained in solution according to NMR and density functional theory (DFT) calculations. The cytotoxic activity of compounds 2 was evaluated against four cancer cell lines and one non-cancerous cell line and several structure-activity correlations were found for these complexes. For instance, the activity decreased when the bulkiness of the R alkyl group in Na 3 [Ag(NHC R ) 2 ] increased. More interesting is the detected chirality-anticancer relationship, where complexes Na 3 [Ag{(S,S)-NHC R } 2 ] (R = Me, 2b; i Pr, 2c) showed better anticancer activity than those of their enantiomeric derivatives Na 3 [Ag{(R,R)-NHC R } 2 ] (R = Me, 2b'; i Pr, 2c')., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: In patients with acute respiratory distress syndrome (ARDS), the PaO2/FiO2 ratio at the time of ARDS diagnosis is weakly associated with mortality. We hypothesized that setting a PaO2/FiO2 threshold in 150 mm Hg at 24 h from moderate/severe ARDS diagnosis would improve predictions of death in the intensive care unit (ICU). Methods: We conducted an ancillary study in 1303 patients with moderate to severe ARDS managed with lung-protective ventilation enrolled consecutively in four prospective multicenter cohorts in a network of ICUs. The first three cohorts were pooled (n = 1000) as a testing cohort; the fourth cohort (n = 303) served as a confirmatory cohort. Based on the thresholds for PaO2/FiO2 (150 mm Hg) and positive end-expiratory pressure (PEEP) (10 cm H2O), the patients were classified into four possible subsets at baseline and at 24 h using a standardized PEEP-FiO2 approach: (I) PaO2/FiO2 ≥ 150 at PEEP < 10, (II) PaO2/FiO2 ≥ 150 at PEEP ≥ 10, (III) PaO2/FiO2 < 150 at PEEP < 10, and (IV) PaO2/FiO2 < 150 at PEEP ≥ 10. Primary outcome was death in the ICU. Results: ICU mortalities were similar in the testing and confirmatory cohorts (375/1000, 37.5% vs. 112/303, 37.0%, respectively). At baseline, most patients from the testing cohort (n = 792/1000, 79.2%) had a PaO2/FiO2 < 150, with similar mortality among the four subsets (p = 0.23). When assessed at 24 h, ICU mortality increased with an advance in the subset: 17.9%, 22.8%, 40.0%, and 49.3% (p < 0.0001). The findings were replicated in the confirmatory cohort (p < 0.0001). However, independent of the PEEP levels, patients with PaO2/FiO2 < 150 at 24 h followed a distinct 30-day ICU survival compared with patients with PaO2/FiO2 ≥ 150 (hazard ratio 2.8, 95% CI 2.2−3.5, p < 0.0001). Conclusions: Subsets based on PaO2/FiO2 thresholds of 150 mm Hg assessed after 24 h of moderate/severe ARDS diagnosis are clinically relevant for establishing prognosis, and are helpful for selecting adjunctive therapies for hypoxemia and for enrolling patients into therapeutic trials.

Background: While searching for novel small molecules for new organic pesticide agents against plant-parasitic nematodes, we found that the hexane extract from the roots of Senecio sinuatos and its main secondary metabolite, 3β-angeloyloxy-6β-hydroxyfuranoeremophil-1(10)-ene (1), possess nematicidal activity against the second stage juvenile (J2) of Meloidogyne incognita and Nacobbus aberrans. Both species reduce yield of various vegetable crops. These results encouraged us to synthesize esters 3-9 formed by diol 2, obtained by alkaline hydrolysis of 1 and acetic anhydride, benzoic acid, 2-nitrobenzoic acid, 2-bromobenzoic acid, 4-nitrobenzoic acid, 4-bromobenzoic acid, and 4-methoxybenzoic acid, respectively. The nematicidal activity of these esters was evaluated and compared with that of the free benzoic acids., Results: Natural product 1 and derivatives 2-9 were obtained and characterized by their physical and spectroscopic properties, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments; X-ray diffraction analysis established their absolute configuration. The nematicidal activity of compounds 1-9 was assessed in vitro against M. incognita and N. aberrans J2 and was compared to activity shown by benzoic acid, 2-nitrobenzoic acid, 2-bromobenzoic acid, 4-nitrobenzoic acid, 4-bromobenzoic acid, and 4-methoxybenzoic acid. The esters suppressed nematodes more than free benzoic acid. Nacobbus aberrans J2 were suppressed, with compounds 5, 6, and 8 being the most active., Conclusion: Esters formed by 3β,6β-dihydroxyfuranoeremophil-1(10)-ene and ortho- or para-substituted benzoic acids containing electron acceptor groups had nematicidal activity against N. aberrans. These compound can potentially serve as a model for the development of new organic nematicidal agents. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

The aerial parts of Ageratina vernalis provided the new germacranolide 1,10-epoxydeltoidin A ( 3 ), together with the known pentacyclic triterpenoid hopane-6 α ,22-diol ( 1 ), and the also known germacranolides deltoidin A ( 2 ) and 15-hydroxydeltoidin A ( 4 ). In addition, p TsOH catalyzed cyclization of 2 afforded the new guaianolide 5 . The absolute configuration of 2 , 4 , and 5 was assigned by vibrational circular dichroism spectroscopy, while the complete 1 H and 13 C NMR data assignments of 2 - 5 followed from 1 D- and 2 D-NMR experiments.

Pt(II) alkylidene 1a has been reacted with terminal alkynes to afford ylide complexes 3a-d, resulting from electrophilic activation of the CC bond and its insertion into the platinacyclic fragment of 1a that contains the carbene functionality. DFT calculations indicate that the observed regioselectivity is determined by the nucleophilic attack of the alkyne to the alkylidene carbon.

Complexes {Ag[NHC Mes,R ]} n (R = H, 2a ; Me, 2b and 2b' ; i Pr, 2c ; i Bu, 2d ), were prepared by treatment of imidazolium precursor compounds [Im Mes,R ] (2-(3-mesityl-1 H -imidazol-3-ium-1-yl)acetate, 1a , ( S )-2- alkyl (3-mesityl-1 H -imidazol-3-ium-1-yl)acetate, 1b - d , and ( R )-2-methyl(3-mesityl-1 H -imidazol-3-ium-1-yl)acetate, 1b' , with Ag 2 O under appropriate conditions. They were characterised by analytical, spectroscopic (IR, 1 H, and 13 C NMR and polarimetry), and X-ray methods ( 2a ). In the solid state, 2a is a one-dimensional coordination polymer, in which the silver(I) cation is bonded to the carbene ligand and to the carboxylate group of a symmetry-related Ag[NHC Mes,H ] moiety. The coordination environment of the silver centre is well described by the DFT study of the dimeric model {Ag[NHC Mes,H ]} 2 . The antimicrobial properties of these complexes were evaluated versus Gram-negative bacteria E. coli and P. aeruginosa . From the observed MIC and MBC values (minimal inhibitory concentration and minimal bactericidal concentration, respectively), complex 2b' showed the best antimicrobial properties (eutomer), which were significantly better than those of its enantiomeric derivative 2b (distomer). Additionally, analysis of MIC and MBC values of 2a - d reveal a clear structure-antimicrobial effect relationship. Antimicrobial activity decreases when the steric properties of the R alkyl group in {Ag[NHC Mes,R ]} n increase.

Complexes [Ag(L R )], 2 (L R = 2,2'-(imidazolium-1,3-diyl)di(2- alkyl acetate)), were prepared by treatment of compounds HL R , 1, with Ag 2 O. They were characterised by analytical, spectroscopic (IR, 1 H and 13 C NMR and polarimetry) and X-ray methods (2c, 2c' and 2e). In the solid state, these compounds are novel one-dimensional or two-dimensional coordination polymers in which silver(I) cations are connected via the chiral [L R ] - anion with unprecedented coordination modes. The antimicrobial properties of these complexes were evaluated. 2a and 2b' showed the best antimicrobial properties (minimal inhibitory concentrations and minimal bactericidal concentration) for Pseudomonas aeruginosa and Escherichia coli pathogens. Eutomers 2b' and 2c' showed slightly better antimicrobial properties than their respective enantiomers 2b and 2c.

Diastereoisomeric stigmasterol oxiranes 4, 5, 8, and 9 are known phytosterol oxidation products (POPs) that have been evaluated for their cytotoxicity, although the results are of limited significance since, in most cases, they were evaluated as mixtures. Consequently, to establish biological activity hierarchy of these oxides, it is critical to evaluate individual pure POPs. Therefore, we now describe the obtention of individual molecules and their absolute configuration (AC) determination. The two acetylated C-5-C-6 oxiranes 6 and 7; the two acetylated C-22-C-23 oxides 10 and 11, obtained by means of Δ 5 double bond protection-deprotection; and the four C-5-C-6, C-22-C-23 diepoxystigmasteryl acetates 19-22 were now individually gained and their AC determined by vibrational circular dichroism. Vibrational modes associated with the C-5-C-6 and the C-22-C-23 bonds were identified in dioxiranes 19-22 and used to assign the AC of monoepoxides 6, 7, 10, and 11. The AC of biological active non-acetylated molecules follows immediately. Due to the scarce spectroscopic information available for these POPs, the 1 H and 13 C NMR chemical shifts of 3-22 were assigned using 1D- and 2D-NMR experiments., (© 2021 Wiley Periodicals LLC.)

Traditional cardiovascular (CV) risk factors (RFs) and coronary artery disease (CAD) do not always show a direct correlation. We investigated the metabolic differences in a cohort of patients with a high CV risk profile who developed, or did not develop, among those enrolled in the Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation (CAPIRE) study. We studied 112 subjects with a high CV risk profile, subdividing them according to the presence (CAD/High-RFs) or absence of CAD (No-CAD/High-RFs), assessed by computed tomography angiography. The metabolic differences between the two groups were identified by gas chromatography-mass spectrometry. Characteristic patterns and specific metabolites emerged for each of the two phenotypic groups: high concentrations of pyruvic acid, pipecolic acid, p-cresol, 3-aminoisobutyric acid, isoleucine, glyceric acid, lactic acid, sucrose, phosphoric acid, trimethylamine-N-oxide, 3-hydroxy-3-methylglutaric acid, erythritol, 3-hydroxybutyric acid, glucose, leucine, and glutamic acid; and low concentrations of cholesterol, hypoxanthine, glycerol-3-P, and cysteine in the CAD/High-RFs group vs the No-CAD/High-RFs group. Our results show the existence of different metabolic profiles between patients who develop CAD and those who do not, despite comparable high CV risk profiles. A specific cluster of metabolites, rather than a single marker, appears to be able to identify novel predisposing or protective mechanisms towards CAD beyond classic CVRFs.

The new labdane [(3R*,4aR*,7S*,10aS*,10bR*)-3-ethenyl-3,4a,7,10a-tetramethyl-dodecahydro-1H-naphtho-[2,1-b]-pyran-7-yl]-methylbenzoate together with other 7 labdanes were isolated from the aerial parts of Buddleja marrubiifolia . Compound structures were elucidated by spectroscopic methods. Some compounds showed moderate to weak antimicrobial activity towards a panel of bacterial and fungal pathogens. In addition, trans -biformene (2) and ribenol acetate (8) showed to be highly cytotoxic with LC50 < 1 µg/mL, the other compounds showed moderate cytotoxic effect with a LC50 range of 6.008-15.26 µg/mL. For all isolated compounds, no inflammatory response was observed.

Metal complexes incorporating proton-responsive ligands have been proved to be superior catalysts in reactions involving the H 2 molecule. In this contribution, a series of Ir III complexes based on lutidine-derived CNN H pincers containing N-heterocyclic carbene and secondary amino NHR [R = Ph ( 4a ), t Bu ( 4b ), benzyl ( 4c )] donors as flanking groups have been synthesized and tested in the dehydrogenation of ammonia-borane (NH 3 BH 3 , AB) in the presence of substoichiometric amounts (2.5 equiv) of t BuOK. These preactivated derivatives are efficient catalysts in AB dehydrogenation in THF at room temperature, albeit significantly different reaction rates were observed. Thus, by using 0.4 mol % of 4a , 1.0 equiv of H 2 per mole of AB was released in 8.5 min (turnover frequency (TOF 50% ) = 1875 h -1 ), while complexes 4b and 4c (0.8 mol %) exhibited lower catalytic activities (TOF 50% = 55-60 h -1 ). 4a is currently the best performing Ir III homogeneous catalyst for AB dehydrogenation. Kinetic rate measurements show a zero-order dependence with respect to AB, and first order with the catalyst in the dehydrogenation with 4a (-d[AB]/d t = k [ 4a ]). Conversely, the reaction with 4b is second order in AB and first order in the catalyst (-d[AB]/d t = k [ 4b ][AB] 2 ). Moreover, the reactions of the derivatives 4a and 4b with an excess of t BuOK (2.5 equiv) have been analyzed through NMR spectroscopy. For the former precursor, formation of the iridate 5 was observed as a result of a double deprotonation at the amine and the NHC pincer arm. In marked contrast, in the case of 4b , a monodeprotonated (at the pincer NHC-arm) species 6 is observed upon reaction with t BuOK. Complex 6 is capable of activating H 2 reversibly to yield the trihydride derivative 7 . Finally, DFT calculations of the first AB dehydrogenation step catalyzed by 5 has been performed at the DFT//MN15 level of theory in order to get information on the predominant metal-ligand cooperation mode.

Extracellular vesicles (EV) derived from mesenchymal stromal cells (MSC) are a potential therapy for immunological and degenerative diseases. However, large-scale production of EV free from contamination by soluble proteins is a major challenge. The generation of particles from isolated membranes of MSC, membrane particles (MP), may be an alternative to EV. In the present study we generated MP from the membranes of lysed MSC after removal of the nuclei. The yield of MP per MSC was 1 × 10 5 times higher than EV derived from the same number of MSC. To compare the proteome of MP and EV, proteomic analysis of MP and EV was performed. MP contained over 20 times more proteins than EV. The proteins present in MP evidenced a multi-organelle origin of MP. The projected function of the proteins in EV and MP was very different. Whilst proteins in EV mainly play a role in extracellular matrix organization, proteins in MP were interconnected in diverse molecular pathways, including protein synthesis and degradation pathways and demonstrated enzymatic activity. Treatment of MSC with IFNγ led to a profound effect on the protein make up of EV and MP, demonstrating the possibility to modify the phenotype of EV and MP through modification of parent MSC. These results demonstrate that MP are an attractive alternative to EV for the development of potential therapies. Functional studies will have to demonstrate therapeutic efficacy of MP in preclinical disease models.

Background: Traditional cardiovascular risk factors (RFs) and coronary artery disease (CAD) do not always run parallel. We investigated functional-metabolic correlations of CAD, RFs, or neither in the CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation) 2 × 2 phenotypic observational study., Methods: Two hundred and fortyone subjects were included based on RF burden, presence/absence of CAD (assessed by computed tomography angiography), age and sex. Participants displayed one of four phenotypes: CAD with ≥3 RFs, no-CAD with ≥3 RFs, CAD with ≤1 RF and no-CAD with ≤1 RF. Metabolites were identified by gas chromatography-mass spectrometry and pathways by metabolite set enrichment analysis., Results: Characteristic patterns and specific pathways emerged for each phenotypic group: amino sugars for CAD/high-RF; urea cycle for no-CAD/high-RF; glutathione for CAD/low-RF; glycine and serine for no-CAD/low-RF. Presence of CAD correlated with ammonia recycling; absence of CAD with the transfer of acetyl groups into mitochondria; high-risk profile with alanine metabolism (all p < 0.05). The comparative case-control analyses showed a statistically significant difference for the two pathways of phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism in the CAD/Low-RF vs NoCAD/Low-RF comparison., Conclusions: The present 2 × 2 observational study identified specific metabolic pathways for each of the four phenotypes, providing novel functional insights, particularly on CAD with low RF profiles and on the absence of CAD despite high-risk factor profiles., Competing Interests: Declaration of Competing Interest, (Copyright © 2021. Published by Elsevier B.V.)

Proinflammatory stimuli lead to endothelial injury, which results in pathologies such as cardiovascular diseases, autoimmune diseases, and contributes to alloimmune responses after organ transplantation. Both mesenchymal stromal cells (MSC) and the extracellular vesicles (EV) released by them are widely studied as regenerative therapy for the endothelium. However, for therapeutic application, the manipulation of living MSC and large-scale production of EV are major challenges. Membrane particles (MP) generated from MSC may be an alternative to the use of whole MSC or EV. MP are nanovesicles artificially generated from the membranes of MSC and possess some of the therapeutic properties of MSC. In the present study we investigated whether MP conserve the beneficial MSC effects on endothelial cell repair processes under inflammatory conditions. MP were generated by hypotonic shock and extrusion of MSC membranes. The average size of MP was 120 nm, and they showed a spherical shape. The effects of two ratios of MP (50,000; 100,000 MP per target cell) on human umbilical vein endothelial cells (HUVEC) were tested in a model of inflammation induced by TNFα. Confocal microscopy and flow cytometry showed that within 24 hours >90% of HUVEC had taken up MP. Moreover, MP ended up in the lysosomes of the HUVEC. In a co-culture system of monocytes and TNFα activated HUVEC, MP did not affect monocyte adherence to HUVEC, but reduced the transmigration of monocytes across the endothelial layer from 138 ± 61 monocytes per microscopic field in TNFα activated HUVEC to 61 ± 45 monocytes. TNFα stimulation induced a 2-fold increase in the permeability of the HUVEC monolayer measured by the translocation of FITC-dextran to the lower compartment of a transwell system. At a dose of 1:100,000 MP significantly decreased endothelial permeability (1.5-fold) respect to TNFα Stimulated HUVEC. Finally, MP enhanced the angiogenic potential of HUVEC in an in vitro Matrigel assay by stimulating the formation of angiogenic structures, such as percentage of covered area, total tube length, total branching points, total loops. In conclusion, MP show regenerative effects on endothelial cells, opening a new avenue for treatment of vascular diseases where inflammatory processes damage the endothelium., Competing Interests: Erasmus MC filed a patent on the use of MP for immunomodulatory purposes. Authors MO-V and EL were employed by Takeda Madrid. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2021 Merino, Sablik, Korevaar, López-Iglesias, Ortiz-Virumbrales, Baan, Lombardo and Hoogduijn.)

Bulky terphenyl phosphane ligands PMe 2 Ar' (Ar' = terphenyl group) facilitate the isolation of zero-valent bis-phosphane complexes of nickel, palladium and platinum. The former show coordination numbers greater than two in the solid state due to the existence of Ni-C arene interactions with the terphenyl fragment.

Mesenchymal stromal cells (MSC) are a promising therapy for inflammatory diseases. However, MSC are large and become trapped in the lungs after intravenous infusion, where they have a short survival time. To steer MSC immunoregulatory therapy beyond the lungs, we generated nm-sized particles from MSC membranes (membrane particles, MP), which have immunomodulatory properties, and investigated their internalization and mode of interaction in macrophages subtypes and human umbilical vein endothelial cells (HUVEC) under control and inflammatory conditions. We found that macrophages and HUVEC take up MP in a dose, time, and temperature-dependent manner. Specific inhibitors for endocytotic pathways revealed that MP internalization depends on heparan sulfate proteoglycan-, dynamin-, and clathrin-mediated endocytosis but does not involve caveolin-mediated endocytosis. MP uptake also involved the actin cytoskeleton and phosphoinositide 3-kinase, which are implicated in macropinocytosis and phagocytosis. Anti-inflammatory M2 macrophages take up more MP than pro-inflammatory M1 macrophages. In contrast, inflammatory conditions did not affect the MP uptake by HUVEC. Moreover, MP induced both anti- and pro-inflammatory responses in macrophages and HUVEC by affecting gene expression and cell surface proteins. Our findings on the mechanisms of uptake of MP under different conditions help the development of target-cell specific MP therapy to modulate immune responses., Competing Interests: MO and EL were employed by Takeda Madrid. Erasmus MC filed a patent on MSC derived MP (PCT/NL2017/050334). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 da Costa Gonçalves, Korevaar, Ortiz Virumbrales, Baan, Reinders, Merino, Lombardo and Hoogduijn.)

The four new briarane diterpenoids 2-butyryloxybriarane B-3 (2), 9-acetylbriarenolide S (3), briarenolide W (4), and 12-isobriarenolide P (5), along with briarane B-3 (1) and the five known diterpenes 6-10 were isolated from the gorgonian coral Briareum asbestinum collected from the Mexican Caribbean Sea. The structures were elucidated by 1D and 2D NMR and MS measurements. Since the structure of briarane B-3 (1) was only suggested and published without any spectroscopic support, it was herein confirmed, and the supporting data are now provided. In addition, 1 provided the opportunity to explore the sensitivity of vibrational circular dichroism (VCD) to determine the configuration of a single stereogenic center in the presence of eight other stereogenic centers in a molecule possessing a highly flexible ten-member ring. A single-crystal X-ray diffraction study, in which the Flack and Hooft parameters of 1 were determined, further confirmed that briarane B-3 is (1S,2S,6S,7R,8R,9S,10S,11R,17R)-1. This paper reports for first time the use of VCD in briarane diterpenes and with the presence of chlorine atoms. Biological evaluation of seven isolated compounds evidenced a moderate anti-inflammatory activity for compounds 6 and 9 but it did not show any cytotoxic, antiviral, antibacterial, and topoisomerase inhibitory activity.

Background: Community-acquired bacterial pneumonia (CABP) can lead to sepsis and is associated with high mortality rates in patients presenting with shock and/or respiratory failure and who require mechanical ventilation and admission to intensive care units, thus reflecting the limited effectiveness of current therapy. Preclinical studies support the efficacy of expanded allogeneic adipose-derived mesenchymal stem cells (eASCs) in the treatment of sepsis. In this study, we aim to test the safety, tolerability and efficacy of eASCs as adjunctive therapy in patients with severe CABP (sCABP)., Methods: In addition to standard of care according to local guidelines, we will administer eASCs (Cx611) or placebo intravenously as adjunctive therapy to patients with sCABP. Enrolment is planned for approximately 180 patients who will be randomised to treatment groups in a 1:1 ratio according to a pre-defined randomization list. An equal number of patients is planned for allocation to each group. Cx611 will be administered on Day 1 and on Day 3 at a dose of 160 million cells (2 million cells / mL, total volume 80 mL) through a 20-30 min (240 mL/hr) intravenous (IV) central line infusion after dilution with Ringer Lactate solution. Placebo (Ringer Lactate) will also be administered through a 20-30 min (240 mL/hr) IV central line infusion at the same quantity (total volume of 80 mL) and following the same schedule as the active treatment. The study was initiated in January 2017 and approved by competent authorities and ethics committees in Belgium, Spain, Lithuania, Italy, Norway and France; monitoring will be performed at regular intervals. Funding is from the European Union's Horizon 2020 Research and Innovation Program., Discussion: SEPCELL is the first trial to assess the effects of eASCs in sCABP. The data generated will advance understanding of the mode of action of Cx611 and will provide evidence on the safety, tolerability and efficacy of Cx611 in patients with sCABP. These data will be critical for the design of future confirmatory clinical investigations and will assist in defining endpoints, key biomarkers of interest and sample size determination., Trial Registration: NCT03158727 , retrospectively registered on 9 May 2017.

Cardiovascular disease (CVD) is the major cause of death in patients with type-2 diabetes mellitus (T2DM), although the factors that accelerate atherosclerosis in these patients are poorly understood. The identification of the altered quantity and quality of lipoproteins, closely related to atherogenesis, is limited in routine to a pattern of high triglycerides and low HDL-cholesterol (HDL-C) and in research as dysfunctional HDLs. We used the emerging NMR-based lipidomic technology to investigate compositional features of the HDLs of healthy individuals with normal coronary arteries, drug-naïve; recently diagnosed T2DM patients with normal coronary arteries; and patients with recent acute coronary syndrome. Patients with T2DM and normal serum lipid profiles even at diagnosis presented significant lipid alterations in HDL, characterized by higher triglycerides, lysophosphatidylcholine and saturated fatty acids; and lower cholesterol, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, plasmalogens and polyunsaturated fatty acids, an atherogenic pattern that may be involved in the pathogenesis of atherosclerosis. These changes are qualitatively similar to those found, more profoundly, in normolipidemic patients with established Coronary Heart Disease (CHD). We also conclude that NMR-based lipidomics offer a novel holistic exploratory approach for identifying and quantifying lipid species in biological matrixes in physiological processes and disease states or in disease biomarker discovery.

Background: Mesenchymal stem cells (MSCs) activate the endogenous immune regulatory system, inducing a therapeutic effect in recipients. MSCs have demonstrated the ability to modulate the differentiation of myeloid cells toward a phagocytic and anti-inflammatory profile. Allogeneic, adipose-derived MSCs (ASCs) have been investigated for the management of complex perianal fistula, with darvadstrocel being the first ASC therapy approved in Europe in March 2018. Additionally, ASCs are being explored as a potential treatment in other indications. Yet, despite these clinical advances, their mechanism of action is only partially understood., Methods: Freshly isolated human monocytes from the peripheral blood were differentiated in vitro toward M0 non-polarized macrophages (Mphs), M1 pro-inflammatory Mphs, M2 anti-inflammatory Mphs, or mature dendritic cells (mDCs) in the presence or absence of ASCs, in non-contact conditions. The phenotype and function of the differentiated myeloid populations were determined by flow cytometry, and their secretome was analyzed by OLINK technology. We also investigated the capacity of ASCs to modulate the phenotype and function of terminally differentiated M1 Mphs. The role of soluble factors interleukin (IL)-6 and prostaglandin E2 (PGE2) on the ability of ASCs to modulate myeloid cells was assessed using neutralization assays, CRISPR/Cas9 knock-down of cyclooxygenase 2 (COX-2), and ASC-conditioned medium assays using pro-inflammatory stimulus., Results: Co-culture of monocytes in the presence of ASCs resulted in the polarization of Mphs and mDCs toward an anti-inflammatory and phagocytic phenotype. This was characterized by an increase in phagocytic receptors on the cell surface of Mphs (M0, M1, and M2) and mDCs, as well as modulation of chemokine receptors and reduced expression of pro-inflammatory, co-stimulatory molecules. ASCs also modulated the secretome of Mphs and mDCs, demonstrated by reduced expression of pro-inflammatory factors and increased expression of anti-inflammatory and reparative factors. Chemical inhibition of PGE2 with indomethacin abolished this modulatory effect, whereas treatment with a neutralizing anti-IL-6 antibody resulted in a partial abolishment. The knock-down of COX-2 in ASCs and the use of IL-1β-activated ASC-conditioned media confirmed the key role of PGE2 in ASC-mediated myeloid modulation. In our in vitro experimental settings, ASCs failed to modulate the phenotype and function of terminally polarized M1 Mphs., Conclusions: The results demonstrate that ASCs are able to modulate the in vitro differentiation of myeloid cells toward an anti-inflammatory and reparative profile. This modulatory effect was mediated mainly by PGE2 and, to a lesser extent, IL-6.

This study analyzes the relationship between the mycobiome of the Lower Respiratory Tract (LRT) and the fungi in the domestic environment. Samples studied consisted of Broncho-Alveolar Lavage (BAL) from 45 patients who underwent bronchoscopy for different diagnostic purposes, and dust and air from the houses (ENV) of 20 of them (44.4%). Additionally, five bronchoscopes (BS) were also analyzed and negative controls were included for every procedure. All samples were processed for DNA extraction and cultures, which were performed in Sabouraud Dextrose and Potato Dextrose Agar. The fungal Internal Transcribed Spacer (ITS2) was sequenced by the Solexa/Illumina system and sequences were analyzed by QIIME 1.8.0 and compared with the UNITE Database for identification. The similarity between the two fungal communities (BAL and ENV) for a specific patient was assessed via the percentage of coincidence in the detection of specific operational taxonomic units (OTUs), and about 75% of co-occurrence was detected between the mycobiome of the LRT and the houses. Cultures confirmed the presence of the core mycobiome species. However, the low rate of isolation from BAL suggests that most of its mycobiome corresponds to non-culturable cells. This likely depends on the patient's immune system activity and inflammatory status.

A rapid and green method for the synthesis of novel N-thiazolidine-2,4-dione isoxazoline derivatives 5 from N-allyl-5-arylidenethiazolidine-2,4-diones 3 as dipolarophiles with arylnitrile oxides via 1,3-dipolar cycloaddition reaction. The corresponding N-allyl substituted dipolarophiles were prepared by one-pot method from thiazolidine-2,4-dione with aldehydes using Knoevenagel condensation followed by N-allylation of thiazolidine-2,4-dione in NaOH aqueous solution under sonication. In addition, the isoxazoline derivatives 5 were synthesized by regioselective and chemoselective 1,3-dipolar cycloaddition using inexpensive and mild NaCl/Oxone/Na 3 PO 4 as a Cl source, oxidant and/or catalyst under ultrasonic irradiation in EtOH/H 2 O (v/v, 2:1) as green solvent. All synthesized products are furnished in good yields in the short reaction time, and then their structures were confirmed by NMR, mass spectrometry and X-ray crystallography analysis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The oxidation of C-H bonds by copper centres in enzymes with molecular oxygen takes place in nature under ambient conditions. Herein we report a similar transformation in which under ambient pressure and temperature (1 atm, 25 °C) the complex TpMsCu(THF) (TpMs = hydrotris(3-mesityl-pyrazol-1-yl)borate) undergoes the intramolecular oxidation of an alkylic C-H bond with O2, leading to the formation of a trinuclear compound where alkoxy and hydroxyl ligands are bonded to the copper centres, as inferred from X-ray studies. The presence of adventitious Cu(0) derived from the partial decomposition of initial TpMsCu(THF) facilitates the formation of such a trinuclear compound. DFT studies support the reaction taking place through a Cu(iii) alkoxy-hydroxyl copper intermediate.

Ru complexes based on lutidine-derived pincer CNN(H) ligands having secondary amine side donors are efficient precatalysts in the hydrogenation and dehydrogenation of N-heterocycles. Reaction of a Ru-CNN(H) complex with an excess of base produces the formation of a Ru(0) derivative, which is observed under catalytic conditions.

The cationic complex [(JohnPhos-Au) 3 (acetylide)][SbF 6 ] (JohnPhos=(2-biphenyl)di-tert-butylphosphine, L1) has been characterised structurally and features an acetylide-trigold(I)-JohnPhos system; the trinuclear-acetylide unit, coordinated to the monodentate bulk phosphines, adopts an unprecedented μ,η 1 ,η 2 ,η 1 coordination mode with an additional interaction between distal phenyl rings and gold centres. Other cationic σ,π-[(gold(I)L1) 2 ] complexes have also been isolated. The reaction of trimethylsilylacetylene with various alcohols (iPrOH, nBuOH, n-HexOH) catalysed by cationic [Au I L1][SbF 6 ] complexes in CH 2 Cl 2 at 50 °C led to the formation of acetaldehyde acetals with a high degree of chemo- and regioselectivity. The reaction mechanism was studied, and several organic and inorganic intermediates have been characterised. A comparative study with the analogous cationic [Cu I L1][PF 6 ] complex revealed different behaviour; the copper metal is lost from the coordination sphere leading to the formation of cationic vinylphosphonium and copper nanoparticles. Additionally, a new catalytic approach for the formation of this high-value cationic vinylphosphonium has been established., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A straightforward method for the preparation of trisphosphinite ligands in one step, using only commercially available reagents (1,1,1-tris(4-hydroxyphenyl)ethane and chlorophosphines) is described. We have made use of this approach to prepare a small family of four trisphosphinite ligands of formula [CH 3 C{(C 6 H 4 OR 2 ) 3 ], where R stands for Ph ( 1a ), Xyl ( 1b , Xyl = 2,6-Me 2 -C 6 H 3 ), i Pr ( 1c ), and Cy ( 1d ). These polyfunctional phosphinites allowed us to investigate their coordination chemistry towards a range of late transition metal precursors. As such, we report here the isolation and full characterization of a number of Au(I), Ag(I), Cu(I), Ir(III), Rh(III) and Ru(II) homotrimetallic complexes, including the structural characterization by X-ray diffraction studies of six of these compounds. We have observed that the flexibility of these trisphosphinites enables a variety of conformations for the different trimetallic species.

We report a series of organometallic nickel and palladium complexes containing iminophosphine ligands R2PCH2C(Ph) = N-Dipp (Dipp = 2,6-diisopropylphenyl; R = iPr, La; R = Ph, Lb; and R = o-C6H4OMe, Lc), synthesized by ligand exchange or oxidative addition reactions, and we investigate the capacity of such ligands to undergo reversible deprotonation to the corresponding phosphinoenaminato species. In the attempted ligand exchange reaction of the nickel bis(trimethylsilyl)methyl precursor [Ni(CH2SiMe3)2Py2] with Lb, the iminophosphine acts as a weak acid rather than a neutral ligand, cleaving one of the Ni-C bonds, to afford the phosphinoenaminato complex [Ni(CH2SiMe3)(L'b)(Py)] (L'b = conjugate base of Lb). We disclose a general method for the syntheses of complexes [Ni(CH2SiMe3)(L)(Py)]+ (L = La, Lb or Lc), and demonstrate that iminophosphine deprotonation is a general feature and occurs reversibly in the coordination sphere of the metal. By studying proton exchange reactions of the cation [Ni(CH2SiMe3)(Lb)(Py)]+ with bases of different strength we show that the conjugate phosphinoenaminato ligand in [Ni(CH2SiMe3)(L'b)(Py)] is a base with strength comparable to DBU in THF. The acyl group in the functionalized aryl complex [Ni(p-C6H4COCH3)(Br)(La)] does not interfere in the iminophosphine deprotonation with NaH. The latter reaction affords the unusual anionic hydroxide species [Ni(p-C6H4COCH3)(OH)(L'a)]-Na+, which was isolated and fully characterized.

Studies exploring the effect of compounds that modulate the endocannabinoid system on sexual behavior have yielded contradictory results. However, the effect of smoked Cannabis in women has been consistently associated with an increase in sexual drive. Therefore, it can be speculated that vaporized Cannabis will augment sexually motivated components of the sexual behavior of female rats. To test this hypothesis, we compared the sexual behavior of late-proestrous female rats in a bilevel chamber after vaporizing 0, 200 or 400 mg of Cannabis flowers (containing 18% of delta-9-THC and undetectable levels of cannabidiol) during 10 min. We found that both doses of Cannabis increased the duration of the lordosis response, whereas the highest dose also reduced the lordosis quotient of females. The lowest dose of Cannabis augmented the display of hops and darts without altering the expression of sexual solicitations of females, while the highest one did not affect the expression of hops and darts but reduced sexual solicitations. These effects were not accompanied by alterations of females' ambulatory behavior. The increment of the duration of lordosis response produced by both doses of Cannabis could be associated to a general effect of this drug in sensory processing, as can be an enhancement of females' sensory reactivity to male's stimulation. However, the reduction in the display of solicitations and lordosis in response to mounting observed in females exposed to the highest dose when compared to control and 200 mg of Cannabis groups indicates a reduction of sexual receptivity and motivation. This differential effect of vaporized Cannabis according to the dose employed, suggests that it modulates sexual behavior in a complex way, impacting neural circuits that control different aspects of this social behavior., (Copyright © 2019 Elsevier Inc. All rights reserved.)

2018 was the year of the first marketing authorization of an allogeneic stem cell therapy by the European Medicines Agency. The authorization concerns the use of allogeneic adipose tissue-derived mesenchymal stromal cells (MSCs) for treatment of complex perianal fistulas in Crohn's disease. This is a breakthrough in the field of MSC therapy. The last few years have, furthermore, seen some breakthroughs in the investigations into the mechanisms of action of MSC therapy. Although the therapeutic effects of MSCs have largely been attributed to their secretion of immunomodulatory and regenerative factors, it has now become clear that some of the effects are mediated through host phagocytic cells that clear administered MSCs and in the process adapt an immunoregulatory and regeneration supporting function. The increased interest in therapeutic use of MSCs and the ongoing elucidation of the mechanisms of action of MSCs are promising indicators that 2019 may be the dawn of the therapeutic era of MSCs and that there will be revived interest in research to more efficient, practical, and sustainable MSC-based therapies. Stem Cells Translational Medicine 2019;8:1126-1134., (© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

A strain isolated from potato common scab superficial lesions in El Fuerte Valley in northern Sinaloa, Mexico, was identified by 16S rRNA and morphological methods. Moreover, the effects of the crude extract of strain V2 was evaluated on radish and potato. The isolate was similar to Streptomyces acidiscabies in its morphological properties; however, the 16S rRNA gene sequence of strain V2 was neither 100% identical to this species nor to the streptomycetes previously reported in Sinaloa, Mexico. Strain V2 did not amplify any specific PCR products for genes nec1 and tomA, which have been found and reported in S. acidiscabies. Strain V2 produced a PCR product for the txtAB operon, which is related to the production of thaxtomin. In vitro assays using crude thaxtomin extract and a spore suspension of the organism caused necrotic symptoms on radish and potato, which were highly virulent in potato. This study reports that Streptomyces sp. V2 has a toxigenic region (TR) that is associated with the thaxtomin gene cluster., (Copyright © 2018 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Adult mesenchymal stem cells (MSCs) improve the host response during experimental sepsis in animals. MSCs from various sources express a procoagulant activity that has been linked to the expression of tissue factor. This study sought to determine the role of tissue factor associated with adipose-derived MSCs (ASCs) in their procoagulant and antibacterial effects during pneumonia-derived sepsis., Methods: Mice were infused intravenously with ASCs or vehicle after infection with the common human pathogen Klebsiella pneumoniae via the airways., Results: Infusion of freshly cultured or cryopreserved ASCs induced the expression of many genes associated with tissue factor signaling and coagulation activation in the lungs. Freshly cultured and cryopreserved ASCs, as well as ASC lysates, exerted procoagulant activity in vitro as determined by a fibrin generation assay, which was almost completely inhibited by an anti-tissue factor antibody. Infusion of cryopreserved ASCs was associated with a rise in plasma thrombin-antithrombin complexes (indicative of coagulation activation) and formation of multiple thrombi in the lungs 4 h post-infusion. Preincubation of ASCs with anti-tissue factor antibody prior to infusion prevented the rise in plasma thrombin-antithrombin complex concentrations but did not influence thrombus formation in the lungs. ASCs reduced bacterial loads in the lungs and liver at 48 h after infection, which was not influenced by preincubation with anti-tissue factor antibody. At this late time point, microthrombi in the lungs were not detected anymore., Conclusion: These data indicate that ASC-associated tissue factor is responsible for systemic activation of coagulation after infusion of ASCs but not for the formation of microthrombi in the lungs or antibacterial effects.

The positive effects of therapeutic human allogeneic cardiac stem/progenitor cells (hCPC) in terms of cardiac repair/regeneration are very likely mediated by paracrine effects. Our previous studies revealed the advantageous immune interactions of allogeneic hCPC and proposed them as part of the positive paracrine effects occurring upon their application postmyocardial infarction (MI). Currently, extracellular vesicles/exosomes (EV/Exs) released by stem/progenitor cells are also proposed as major mediators of paracrine effects of therapeutic cells. Along this line, we evaluated contribution of EV/Exs released by therapeutic hCPC to the benefit of their successful allogeneic clinical application. Through tailored allogeneic in vitro human assay models mimicking the clinical setting, we demonstrate that hCPC-released EV/Exs were rapidly and efficiently up-taken by chief cellular actors of cardiac repair/regeneration. This promoted MAPK/Erk1/2 activation, migration, and proliferation of human leukocyte antigens (HLA)-mismatched hCPC, mimicking endogenous progenitor cells and cardiomyocytes, and enhanced endothelial cell migration, growth, and organization into tube-like structures through activation of several signaling pathways. EV/Exs also acted as pro-survival stimuli for HLA-mismatched monocytes tuning their phenotype toward an intermediate anti-inflammatory pro-angiogenic phenotype. Thus, while positively impacting the intrinsic regenerative and angiogenic programs, EV/Exs released by therapeutic allogeneic hCPC can also actively contribute to shaping MI-inflammatory environment, which could strengthen the benefits of hCPC allogeneic interactions. Collectively, our data might forecast the application of allogeneic hCPC followed by their cell-free EV/Exs as a strategy that will not only elicit the cell-contact mediated reparative/regenerative immune response but also have the desired long-lasting effects through the EV/Exs. Stem Cells Translational Medicine 2019;8:911&924., (© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

A new family of sulfinamide/sulfoxide derivatives was synthesized as chiral bidentate ligands by stereoselective additions of methylsulfinyl carbanions to N-tert -butylsulfinylimines. The new ligands, with C 1 , pseudo- meso , and pseudo- C 2 symmetries, were successfully assayed in Rh-catalyzed additions of arylboronic acids to activated ketones. The sterically dissymmetric C 1 ligand ( R S , S C , R S )- N -[1-(phenylsulfinyl)-3-methylbut-2-yl] tert -butylsulfinamide turned out to be the optimal one, allowing the 1,4-additions of diverse arylboronic acids, on different α,β-unsaturated cyclic ketones with high chemical yields and enantioselectivities up to >99% ee.

Adult mesenchymal stem cells exert immunomodulatory effects that might improve the host response during sepsis. Knowledge on the effect of adipose-derived mesenchymal stem cells (ASCs) in sepsis is limited. Klebsiella (K.) pneumoniae is a common cause of gram-negative pneumonia and sepsis. This study sought to determine the effect of human ASCs on the host response during pneumosepsis in mice. Mice were infected with K. pneumoniae via the airways to induce a gradually evolving infection in the lung culminating pneumosepsis. One or 6 hours after infection, mice were infused intravenously with ASCs or vehicle, and euthanized after 16 hours or 48 hours, respectively. The effects of freshly cultured and cryopreserved ASCs were compared, the latter formulation being more clinically relevant. Intravenously administered ASCs were visualized in lung tissue by immunostaining at 1 and 3 hours, but not at 15 hours after infusion. Although early after infection, ASCs did not or only modestly influence bacterial loads, they reduced bacterial burdens in lungs and distant organs at 48 hours. ASCs reduced the lung levels of pro-inflammatory cytokines and attenuated lung pathology, but did not influence distant organ injury. ASCs strongly modified the lung transcriptome in uninfected mice and especially mice with pneumosepsis. Cryopreserved and cultured ASCs induced largely similar effects on the lung transcriptome. These data indicate that human ASCs induce profound immune modulatory effects in the lungs, resulting in reduced bacterial burdens and lung inflammation during pneumosepsis caused by a common human pathogen, suggesting that ASCs may be an adjunctive therapeutic in this condition. Stem Cells Translational Medicine 2019;8:785&796., (© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Chiral Na[(S)-L R ] (R = Me, 1a; i Pr, 1b; CH 2 i Pr, 1c, and (S)- sec Bu, 1d) and Na[(R)-L R ] (R = Me, 1a') compounds were synthesised following standard procedures. New compounds 1d and 1a' were analytically and spectroscopically characterised. 1a and 1c were structurally identified by single-crystal X-ray diffraction methods as homochiral 2D coordination polymers, {Na(H 2 O)[(S)-L Me ]} n and {Na[(S)-L CH 2 i Pr ]} n , respectively. Both (S)-2alkyl,2-(1H-imidazol-1-yl)acetate anions displayed unprecedented coordination modes in these coordination polymers: μ 3 κ 2 OκO' for 1a and μ 4 κ 2 Oκ 2 O' for 1c. Enantiomeric species 1a', {Na(H 2 O)[(R)-L Me ]} n , showed the same X-ray powder diffractogram (XRPD) as 1a, in agreement with a similar crystal structure. DFT calculations on the [L R ] - anions confirmed their coordination capabilities as ditopic linkers. In fact, the reaction of Na[L R ] with several metal salts yielded the following coordination polymers: {Ag[(S)-L Me ]} n , 2a, {Ag[(R)-L Me ]} n , 2a', {Cu[(S)-L R ] 2 } n (R = Me, 3a; i Pr, 3b), {Cu[(R)-L Me ]} n , 3a', {Zn[(S)-L R ] 2 } n (R = Me, 4a; i Pr, 4b; (S)- sec Bu, 4d) and {Zn[(R)-L Me ] 2 } n , 4a'. For the known compounds 3a and 4a, this procedure is a new synthetic route that avoided high temperature reaction conditions. New complexes 2, 3a', b, and 4a', b, d were characterised by elemental analysis, infrared and XRPD methods and complex 2a by single-crystal X-ray diffraction. This complex is also a two-dimensional coordination polymer in which the [(S)-L Me ] - anion acts as a μ 4 κN,κ 2 O,κ 2 O' bridging ligand. Compounds 1-4a' are the first examples of homochiral coordination polymers with imidazole-monocarboxylate ligands based on non-natural amino acids. Preliminary studies on the metal-catalysed preparation of chiral α-aminophosphonates were carried out but, unfortunately, no enantioselectivity was observed.

A family of stable and otherwise selectively unachievable 2,6-bisimino-4-R-1,4-dihydropyridinate aluminium (III) dialkyl complexes [AlR'2(4-R-iPrBIPH)] (R = Bn, Allyl; R' = Me, Et, iBu) have been synthesized, taking advantage of a method for the preparation of the corresponding 4-R-1,4-dihydropiridine precursors developed in our group. All the dihydropyrdinate(-1) dialkyl aluminium complexes have been fully characterized by 1H- 13C-NMR, elemental analysis and in the case 2'a, also by X-ray diffraction studies. Upon heating in toluene solution at 110 °C, the dimethyl derivatives 2a and 2'a dimerize selectively through a double cycloaddition. This reaction leads to the formation of two new C-C bonds that involve the both meta positions of the two 4-R-1,4-dihydropyridinate fragments, resulting the binuclear aluminium species [Me2Al(4-R-iPrHBIP)]2 (R = Bn (3a); allyl (3'a)). Experimental kinetics showed that the dimerization of 2'a obeys second order rate with negative activation entropy, which is consistent with a bimolecular rate-determining step. Controlled methanolysis of both 3a and 3'a release the metal-free dimeric bases, (4-Bn-iPrHBIPH)2 and (4-allyl-iPrHBIPH)2, providing a convenient route to these potentially useful ditopic ligands. When the R' groups are bulkier than Me (2b, 2'b and 2'c), the dimerization is hindered or fully disabled, favoring the formation of paramagnetic NMR-silent species, which have been identified on the basis of a controlled methanolysis of the final organometallic products. Thus, when a toluene solution of [AlEt2(4-Bn-iPrBIPH)] (2b) was heated at 110 °C, followed by the addition of methanol in excess, it yields a mixture of the dimer (4-Bn-iPrHBIPH)2 and the aromatized base 4-Bn-iPrBIP, in ca. 1 : 2 ratio, indicating that the dimerization of 2b competes with its spontaneous dehydrogenation, yielding a paramagnetic complex containing a AlEt2 unit and a non-innocent (4-Bn-iPrBIP)˙- radical-anion ligand. Similar NMR monitoring experiments on the thermal behavior of [AlEt2(4-allyl-iPrBIPH)] (2'b) and [AliBu2(4-allyl-iPrBIPH)] (2'c) showed that these complexes do not dimerize, but afford exclusively NMR silent products. When such thermally treated samples were subjected to methanolysis, they resulted in mixtures of the alkylated 4-allyl-iPrBIP and non-alkylated iPrBIP ligand, suggesting that dehydrogenation and deallylation reactions take place competitively.

Adipose mesenchymal stem cells (ASC) are considered minimally immunogenic. This is due to the low expression of human leukocyte antigens I (HLA-I), lack of HLA-II expression and low expression of co-stimulatory molecules such as CD40 and CD80. The low rate of observed immunological rejection as well as the immunomodulatory qualities, position ASC as a promising cell-based therapy for the treatment of a variety of inflammatory indications. Yet, few studies have addressed relevant aspects of immunogenicity such as ASC donor-to-patient HLA histocompatibility or assessment of immune response triggered by ASC administration, particularly in the cases of presensitization. The present study aims to assess allo-immune responses in a cohort of Crohn's disease patients administered with allogeneic ASC (darvadstrocel formerly Cx601) for the treatment of complex perianal fistulas. We identified donor-specific antibodies (DSA) generation in a proportion of patients and observed that patients showing preexisting immunity were prone to generating DSA after allogeneic therapy. Noteworthy, naïve patients generating DSA at week 12 (W12) showed a significant reduction in DSA titer at week 52 (W52), whereas DSA titer was reduced in pre-sensitized patients only with no specificities against the donor administered. Remarkably, we did not observe any correlation of DSA generation with ASC therapeutic efficacy. In vitro complement-dependent cytotoxicity (CDC) studies have revealed limited cytotoxic levels based upon HLA-I expression and binding capacity even in pro-inflammatory conditions. We sought to identify CDC coping mechanisms contributing to the limited cytotoxic killing observed in ASC in vitro . We found that ASC express membrane-bound complement regulatory proteins (mCRPs) CD55, CD46, and CD59 at basal levels, with CD46 more actively expressed in pro-inflammatory conditions. We demonstrated that CD46 is a main driver of CDC signaling; its depletion significantly enhances sensitivity of ASC to CDC. In summary, despite relatively high clearance, DSA generation may represent a major challenge for allogeneic cell therapy management. Sensitization may be a significant concern when evaluating re-treatment or multi-donor trials. It is still unknown whether DSA generation could potentially be the consequence of donor-to-patient interaction and, therefore, subsequently link to efficacy or biological activity. Lastly, we propose that CDC modulators such as CD46 could be used to ultimately link CDC specificity with allogeneic cell therapy efficacy.