Density Functional Theory-Inspired Design of Ir/P,S-Catalysts for Asymmetric Hydrogenation of Olefins

In silico-based optimization of Ir/P,S-catalysts for the asymmetric hydrogenation of unfunctionalized olefins using (E)-1-(but-2-en-2-yl)-4-methoxybenzene as a benchmark olefin has been carried out. DFT calculations revealed that the thioether group has a major role in directing the olefin coordination. This, together with the configuration of the biphenyl phosphite group, has an impact in maximizing the energy gap between the most stable transition states leading to opposite enantiomers. As a result, the optimized catalyst proved to be efficient in the hydrogenation of a range of alkenes with the same substitution pattern and olefin geometry as the benchmark olefin, regardless of the presence of functional groups with different coordination abilities (ee values up to 97%). Appealingly, further modifications at the thioether groups and at the biaryl phosphite moiety allowed the highly enantioselective hydrogenation of olefins with different substitution patterns (e.g., α,β-unsaturated lactones and lactams, 1,1′-disubstituted enol phosphinates, and cyclic β-enamides; ee values up to >99%).We gratefully acknowledge financial support from the Spanish Ministry of Science and Innovation (PID2019-104904GB-I00, PGC2018-100780-B-I00, and PGC2018-096616-B-I00), European Regional Development Fund (AEI/FEDER, UE), the Catalan Government (2017SGR1472), and the University of Alicante (VOGROB-316FI). M.B. also thanks the URV for generous support

A computational study on the intriguing mechanisms of the gas-phase thermal activation of methane by bare [Ni(H)(OH)](+)

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.A detailed computational study on the reaction mechanisms of the thermal activation of methane by the bare complex [Ni(H)(OH)]+ has been conducted. The experimentally observed reaction features, i.e. the ligand exchange Ni(H) → Ni(CH3), the H/D scrambling between the incoming methane and the hydrido ligand of the nickel complex, the spectator-like behavior of the OH ligand, and the relatively moderate reaction efficiency of 6% relative to the collision rate of the ion/molecule reaction, can be explained by considering three competing mechanisms, and a satisfactory agreement between experiment and theory has been found.DFG, EXC 314, Unifying Concepts in Catalysi

MitoSegNet: Easy-to-use Deep Learning Segmentation for Analyzing Mitochondrial Morphology

While the analysis of mitochondrial morphology has emerged as a key tool in the study of mitochondrial function, efficient quantification of mitochondrial microscopy images presents a challenging task and bottleneck for statistically robust conclusions. Here, we present Mitochondrial Segmentation Network (MitoSegNet), a pretrained deep learning segmentation model that enables researchers to easily exploit the power of deep learning for the quantification of mitochondrial morphology. We tested the performance of MitoSegNet against three feature-based segmentation algorithms and the machine-learning segmentation tool Ilastik. MitoSegNet outperformed all other methods in both pixelwise and morphological segmentation accuracy. We successfully applied MitoSegNet to unseen fluorescence microscopy images of mitoGFP expressing mitochondria in wild-type and catp-6ATP13A2 mutant C. elegans adults. Additionally, MitoSegNet was capable of accurately segmenting mitochondria in HeLa cells treated with fragmentation inducing reagents. We provide MitoSegNet in a toolbox for Windows and Linux operating systems that combines segmentation with morphological analysis

Computationally Guided Design of a Readily Assembled Phosphite- Thioether Ligand for a Broad Range of Pd-Catalyzed Asymmetric Allylic Substitutions

A modular approach employing indene as common starting material, has enabled the straightforward preparation in three reaction steps of P-thioether ligands for the Pd-catalyzed asymmetric allylic substitution. The analysis of a starting library of P-thioether ligands based on rational design and theoretical calculations has led to the discovery of an optimized anthracenethiol derivative with excellent behavior in the reaction of choice. Improving most approaches reported to date, this ligand presents a broad substrate and nucleophile scope. Excellent enantioselectivities have been achieved for a range of linear and cyclic allylic substrates using a large number of C-, N-, and O-nucleophiles (40 compounds in total). The species responsible for the catalytic activity have been further investigated by NMR in order to clearly establish the origin of the enantioselectivity. The resulting products have been derivatized by means of ring-closing metathesis or Pauson–Khand reactions to further prove the synthetic versatility of the methodology for preparing enantiopure complex structures

Citicoline may prevent cognitive decline in patients with cerebrovascular disease

Introduction: Neuroprotective drugs such as citicoline could improve cognitive performance and quality of life. We studied the effect of citicoline treatment and its association with Vascular Risk Factors (VRF) and APOE on cognition in patients with Subjective Cognitive Complaints (SCC) and Mild Cognitive Impairment (MCI). Methods: This is an observational and prospective study with citicoline during 12 months follow-up. Eighty-one subjects who met criteria for SCC/MCI, aged 50–75 years with VRF were included and prescribed citicoline 1g/day. Subjects with previous cognitive impairment and any other central nervous system affection were excluded. Wilcoxon Signed Ranks test and paired samples t-test were used to analyze the change in neuropsychological performance. Results: Mean age of the sample was 68.2 (SD 6.8) years and 26 (32.09%) were females. Fifteen subjects (24.6%) were APOE-ε4 carriers, fifty-six (76.7%) had hypertension, fifty-eight (79.5%) had dyslipidemia, twenty-one (28.8%) had diabetes mellitus and twenty-six (35.6%) had cardiopathy. Thirty-two (43.8%) subjects were diagnosed as SCC and forty-one (56.16%) as MCI. During the follow-up, Tweny-six patients (81.25%) in the group of SCC remained stable, six subjects (18.8%) converted to MCI. Twelve patients (29.9%) with MCI reverted to SCC and twenty-nine patients (70.7%) remained stable. At follow-up, SCC subjects had an improvement in the global language domain (p=0.03), naming (p<0.001), attention (p=0.01) and visuospatial abilities (p<0.01). MCI group showed an improvement in the screening test (p=0.03), delayed memory (p<0.01), global cognition (p=0.04) and in cognitive flexibility (p=0.03). Presence of APOE-ε4 had no impact on the above findings. Discussion: SCC subjects showed an improvement in language and attention domains, while those with MCI performed better after 12 months in total scores of MoCA and RBANS domains, some converting back to SCC. This supports the idea that citicoline may prevent cognitive decline in patients with cognitive deficits

“The burden of post-acute COVID-19 symptoms in a multinational network cohort analysis”

Persistent symptoms following the acute phase of COVID-19 present a major burden to both the affected and the wider community. We conducted a cohort study including over 856,840 first COVID-19 cases, 72,422 re-infections and more than 3.1 million first negative-test controls from primary care electronic health records from Spain and the UK (Sept 2020 to Jan 2022 (UK)/March 2022 (Spain)). We characterised post-acute COVID-19 symptoms and identified key symptoms associated with persistent disease. We estimated incidence rates of persisting symptoms in the general population and among COVID-19 patients over time. Subsequently, we investigated which WHO-listed symptoms were particularly differential by comparing their frequency in COVID-19 cases vs. matched test-negative controls. Lastly, we compared persistent symptoms after first infections vs. reinfections.Our study shows that the proportion of COVID-19 cases affected by persistent post-acute COVID-19 symptoms declined over the study period. Risk for altered smell/taste was consistently higher in patients with COVID-19 vs test-negative controls. Persistent symptoms were more common after reinfection than following a first infection. More research is needed into the definition of long COVID, and the effect of interventions to minimise the risk and impact of persistent symptoms.</p

“The burden of post-acute COVID-19 symptoms in a multinational network cohort analysis”

Persistent symptoms following the acute phase of COVID-19 present a major burden to both the affected and the wider community. We conducted a cohort study including over 856,840 first COVID-19 cases, 72,422 re-infections and more than 3.1 million first negative-test controls from primary care electronic health records from Spain and the UK (Sept 2020 to Jan 2022 (UK)/March 2022 (Spain)). We characterised post-acute COVID-19 symptoms and identified key symptoms associated with persistent disease. We estimated incidence rates of persisting symptoms in the general population and among COVID-19 patients over time. Subsequently, we investigated which WHO-listed symptoms were particularly differential by comparing their frequency in COVID-19 cases vs. matched test-negative controls. Lastly, we compared persistent symptoms after first infections vs. reinfections.Our study shows that the proportion of COVID-19 cases affected by persistent post-acute COVID-19 symptoms declined over the study period. Risk for altered smell/taste was consistently higher in patients with COVID-19 vs test-negative controls. Persistent symptoms were more common after reinfection than following a first infection. More research is needed into the definition of long COVID, and the effect of interventions to minimise the risk and impact of persistent symptoms.</p

Descripció i consens dels criteris de complexitat assistencial i nivells d’intervenció en l’atenció al final de la vida

Nivells assistencials; Atenció al final de la vida; Malalts terminalsNiveles asistenciales; Atención al final de la vida; Enfermos terminalesWelfare levels; Attention to the end of life; Terminally illAquest document pretén ser una eina que faciliti l’organització de l’atenció al final de la vida de la persona amb malaltia avançada/terminal i la seva família, especialment pel que fa a la coordinació entre recursos i l’adequació en la utilització de serveis. L’enfocament no es basa en l’orientació diagnòstica ni en el pronòstic vital de la persona, sinó en la selecció, com a població diana, de les deu patologies proposades per McNamara en la seva estimació de mínims. Aquestes deu patologies són: càncer, insuficiència cardíaca, insuficiència hepàtica, insuficiència renal, insuficiència respiratòria, esclerosi lateral amiotròfica (malalties de la motoneurona), malaltia de Parkinson, corea de Huntington, malaltia d’Alzheimer (demències) i sida. D’acord amb els objectius prioritaris de la línia estratègica del Pla director sociosanitari d’atenció al final de la vida, també s’ha considerat oportú considerar com a subjectes d’atenció especial els pacients geriàtrics pluripatològics, els afectats d’insuficiència orgànica crònica avançada, els pacients amb malalties neurodegeneratives i els malalts de sida. Aquest document planteja un pas més en l’evolució de les cures pal·liatives i s’orienta cap a la complexitat de les diferents necessitats i característiques que pot presentar la persona amb malaltia avançada/terminal i la seva família. Per primera vegada, es disposa d’un document de consens en què es defineixen diferents nivells de complexitat associats amb les necessitats globals de la persona i la seva família i es proposa la intervenció de cadascun dels nivells assistencials del sistema sanitari català amb què compta l’atenció al final de la vida

Incident Use of Hydroxychloroquine for the Treatment of Rheumatoid Arthritis and Systemic Lupus Erythematosus During the COVID-19 Pandemic

Objective: We studied whether the use of hydroxychloroquine (HCQ) for COVID-19 resulted in supply shortages for patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Methods: We used US claims data (IQVIA PHARMETRICS® Plus for Academics [PHARMETRICS]) and hospital electronic records from Spain (Institut Municipal d'Assistència Sanitària Information System [IMASIS]) to estimate monthly rates of HCQ use between January 2019 and March 2022, in the general population and in patients with RA and SLE. Methotrexate (MTX) use was estimated as a control. Results: More than 13.5 million individuals (13,311,811 PHARMETRICS, 207,646 IMASIS) were included in the general population cohort. RA and SLE cohorts enrolled 135,259 and 39,295 patients, respectively, in PHARMETRICS. Incidence of MTX and HCQ were stable before March 2020. On March 2020, the incidence of HCQ increased by 9- and 67-fold in PHARMETRICS and IMASIS, respectively, and decreased in May 2020. Usage rates of HCQ went back to prepandemic trends in Spain but remained high in the United States, mimicking waves of COVID-19. No significant changes in HCQ use were noted among patients with RA and SLE. MTX use rates decreased during HCQ approval period for COVID-19 treatment. Conclusion: Use of HCQ increased dramatically in the general population in both Spain and the United States during March and April 2020. Whereas Spain returned to prepandemic rates after the first wave, use of HCQ remained high and followed waves of COVID-19 in the United States. However, we found no evidence of general shortages in the use of HCQ for both RA and SLE in the United States.</p

Counteranion-Dependent Reaction Pathways in the Protonation of Cationic Ruthenium−Vinylidene Complexes

The tetraphenylborate salts of the cationic vinylidene complexes [Cp*Ru=C=CHR(iPr2PNHPy)]+ (R = p-C6H4CF3 (1a-BPh4), Ph (1b-BPh4), p-C6H4CH3 (1c- BPh4), p-C6H4Br (1d-BPh4), tBu (1e-BPh4), H (1f-BPh4)) have been protonated using an excess of HBF4·OEt2 in CD2Cl2, furnishing the dicationic carbyne complexes [Cp*Ru≡CCH2R(iPr2PNHPy)]2+ (R = p-C6H4CF3 (2a), Ph (2b), p-C6H4CH3 (2c), p-C6H4Br (2d), tBu (2e), H (2f)), which were characterized in solution at low temperature by NMR spectroscopy. The corresponding reaction of the chloride salts 1a-Cl, 1b-Cl, 1c-Cl, and 1d-Cl followed a different pathway, instead affording the novel alkene complexes [Cp*RuCl(κ1(N),η2(C,C)-C5H4N-NHPiPr2CH=CHR)][BF4] (3a−d). In these species, the entering proton is located at the α- carbon atom of the former vinylidene ligand, which also forms a P−C bond with the phosphorus atom of the iPr2PNHPy ligand. To shed light on the reaction mechanism, DFT calculations have been performed by considering several protonation sites. The computational results suggest metal protonation followed by insertion. The coordination of chloride to ruthenium leads to alkenyl species which can undergo a P−C coupling to yield the corresponding alkene complexes. The noncoordinating nature of [BPh4]− does not allow the stabilization of the unsaturated species coming from the insertion step, thus preventing this alternative pathway