Two squares in a barrel: An axially disubstituted conformationally rigid aliphatic binding motif for cucurbit[6]uril

Novel binding motifs suitable for the construction of multitopic guest-based molecular devices (e.g., switches, sensors, data storage, and catalysts) are needed in supramolecular chemistry. No rigid, aliphatic binding motif that allows for axial disubstitution has been described for cucurbit[6]uril (CB6) so far. We prepared three model guests combining spiro[3.3]heptane and bicyclo[1.1.1]pentane centerpieces with imidazolium and ammonium termini. We described their binding properties toward CB6/7 and α-/β-CD using NMR, titration calorimetry, mass spectrometry, and single-crystal X-ray diffraction. We found that a bisimidazolio spiro[3.3]heptane guest forms inclusion complexes with CB6, CB7, and β-CD with respective association constants of 4.0 × 104, 1.2 × 1012, and 1.4 × 102. Due to less hindering terminal groups, the diammonio analogue forms more stable complexes with CB6 (K = 1.4 × 106) and CB7 (K = 3.8 × 1012). The bisimidazolio bicyclo[1.1.1]pentane guest forms a highly stable complex only with CB7 with a K value of 1.1 × 1011. The high selectivity of the new binding motifs implies promising potential in the construction of multitopic supramolecular components.Internal Funding Agency of Tomas Bata University, (IGA/FT/2023/001); Ministerstvo Školství, Mládeže a Tělovýchovy, MŠMT, (LM2023042, LUAUS23144); Ústav organické chemie a biochemie Akademie věd České republiky, ÚOCHB AV ČR, (RVO: 61388963)Internal Funding Agency of Tomas Bata University in Zlin [IGA/FT/2023/001]; MEYS CR [LM2023042]; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences [RVO: 61388963]; Ministry of Education, Youth and Sports [LUAUS23144

Interaction between Macrophages and Human Mesenchymal Stromal Cells Derived from Bone Marrow and Wharton’s Jelly—A Comparative Study

Despite intensive clinical research on the use of mesenchymal stromal cells (MSCs), further basic research in this field is still required. Herein, we compared human bone marrow MSCs (BM-MSCs, n = 6) and Wharton’s jelly MSCs (WJ-MSCs, n = 6) in their ability to interact with human primary macrophages. Evaluation of secretory potential revealed that under pro-inflammatory stimulation, WJ-MSCs secreted significantly more IL-6 than BM-MSCs (2-fold). This difference did not translate into the effect of MSCs on macrophages: both types of MSCs significantly directed M1-like macrophages toward the M2 phenotype (based on CD206 expression) to a similar extent. This observation was consistent both in flow cytometry analysis and immunocytochemical assessment. The effect of MSCs on macrophages was sustained when IL-6 signaling was blocked with Tocilizumab. Macrophages, regardless of polarization status, enhanced chemotaxis of both BM-MSCs and WJ-MSCs (p < 0.01; trans-well assay), with WJ-MSCs being significantly more responsive to M1-derived chemotactic signals than BM-MSCs. Furthermore, WJ-MSCs increased their motility (scratch assay) when exposed to macrophage-conditioned medium while BM-MSCs did not. These results indicate that although both BM-MSCs and WJ-MSCs have the ability to reciprocally interact with macrophages, the source of MSCs could slightly but significantly modify the response under clinical settings

Echo-guided left ventricular assist device speed optimisation for exercise maximisation

OBJECTIVE: Current generation left ventricular assist devices (LVADs) operate with a fixed rotation speed and no automated speed adjustment function. This study evaluates the concept of physiological pump speed optimisation based on aortic valve opening (AVO) imaging during a cardiopulmonary exercise test (CPET). METHODS: This prospective crossover study (NCT05063006) enrolled patients with implanted third-generation LVADs with hydrodynamic bearing. After resting speed optimisation, patients were randomised to a fixed-modified speed or modified-fixed speed CPET sequence. Fixed speed CPET maintained baseline pump settings. During the modified speed CPET, the LVAD speed was continuously altered to preserve periodic AVO. RESULTS: We included 22 patients, the mean age was 58.4±7 years, 4.5% were women and 54.5% had ischaemic cardiomyopathy. Exertional AVO assessment was feasible in all subjects. Maintaining periodic AVO allowed to safely raise the pump speed from 2900 (IQR 2640–3000) to 3440 revolutions per minute (RPM) (IQR 3100–3700; p<0.001). As a result, peak oxygen consumption increased from 11.1±2.4 to 12.8±2.8 mL/kg/min (p<0.001) and maximum workload from 1.1 (IQR 0.9–1.5) to 1.2 W/kg (IQR 0.9–1.7; p=0.028). The Borg scale exertion level decreased from 15.2±1.5 to 13.5±1.2 (p=0.005). CONCLUSIONS: Transthoracic AVO imaging is possible during CPETs in patients with LVAD. Dynamic echo-guided pump speed adjustment based on the AVO improves exercise tolerance and augments peak oxygen consumption and maximum workload

Electrochemical Oxidation of [1-X-12-I-CB₁₁Me₁₀^–] Anions: Formation of Borenium Ylides [12-Dehydro-1-X-CB₁₁Me₁₀] and Iodonium Ylide Anions [{12-(1-X-CB₁₁Me₁₀^–)}₂I⁺]

Cyclic voltammograms of 12-iodinated icosahedral carborane anions [1-X-12-I-CB₁₁Me₁₀^–] (X = H, CH₃, C₂H₅, C₃H₇, C₄H₉, C₆H₁₃, and COOCH₃) show two one-electron anodic oxidation peaks at the Pt electrode in liquid SO₂. Oddly, the first is irreversible and the second partially reversible. Mass spectrometry of the principal anionic product of preparative anodic oxidation of [1-H-12-I-CB₁₁Me₁₁^–], identical with the anionic product of its reaction with [Et₃Si–H–SiEt₃]⁺ and/or Et₃Si⁺, allows it to be identified as the iodonium ylide anion [{12-(1-H-CB₁₁Me₁₀^–)}₂I⁺]. Its reversible oxidation to a neutral ylide radical [{12-(1-H-CB₁₁Me₁₀^•)}­{12-(1-H-CB₁₁Me₁₀^–)}­I⁺] is responsible for the second peak. A DFT geometry optimization suggests that both the ylide anion and the ylide radical are very crowded and have an unusually large C–I–C valence angle of ∼132°; they are the first compounds with two bulky highly methylated CB₁₁ cages attached to the same atom. Molecular iodine is another product of the electrolysis. We propose an electrode mechanism in which initial one-electron oxidation of [1-X-12-I-CB₁₁Me₁₀^–] is followed by a transfer of an iodine atom from the B–I bond to SO₂ to yield a weakly bound radical ISO₂^• which disproportionates into SO₂ and I₂. The other product is the borenium ylide [12-dehydro-1-X-CB₁₁Me₁₀], which has a strongly Lewis acidic naked vertex in position 12 that rapidly adds to another [1-X-12-I-CB₁₁Me₁₀^–] anion to form the observed stable ylide anion [{12-(1-X-CB₁₁Me₁₀^–)}₂I⁺]. In acetonitrile, where it presumably exists as a solvent adduct, [12-dehydro-1-X-CB₁₁Me₁₀] has been trapped with H₂O and, to a small extent, with MeOH, but not with several other potential trapping agents

Patients with Neurodegenerative Proteinopathies Exhibit Altered Tryptophan Metabolism in the Serum and Cerebrospinal Fluid

Some pathological conditions affecting the human body can also disrupt metabolic pathways and thus alter the overall metabolic profile. Knowledge of metabolic disturbances in specific diseases could thus enable the differential diagnosis of otherwise similar conditions. This work therefore aimed to comprehensively characterize changes in tryptophan metabolism in selected neurodegenerative diseases. Levels of 18 tryptophan-related neuroactive substances were determined by high throughput and sensitive ultrahigh-performance liquid chromatography–tandem mass spectrometry in time-linked blood serum and cerebrospinal fluid samples from 100 age-matched participants belonging to five cohorts: healthy volunteers (n = 21) and patients with Lewy body disease (Parkinson’s disease and dementia with Lewy bodies; n = 31), four-repeat tauopathy (progressive supranuclear palsy and corticobasal syndrome; n = 10), multiple system atrophy (n = 13), and Alzheimer’s disease (n = 25). Although these conditions have different pathologies and clinical symptoms, the discovery of new biomarkers is still important. The most statistically significant differences (with p-values of ≤0.05 to ≤0.0001) between the study cohorts were observed for three tryptophan metabolites: l-kynurenine in cerebrospinal fluid and 3-hydroxy-l-kynurenine and 5-hydroxy-l-tryptophan in blood serum. This led to the discovery of distinctive correlation patterns between the profiled cerebrospinal fluid and serum metabolites that could provide a basis for the differential diagnosis of neurodegenerative tauopathies and synucleinopathies. However, further large-scale studies are needed to determine the direct involvement of these metabolites in the studied neuropathologies, their response to medication, and their potential therapeutic relevance

An extended bioreaction database that significantly improves reconstruction and analysis of genome-scale metabolic networks.

The bioreaction database established by Ma and Zeng (Bioinformatics, 2003, 19, 270-277) for in silico reconstruction of genome-scale metabolic networks has been widely used. Based on more recent information in the reference databases KEGG LIGAND and Brenda, we upgrade the bioreaction database in this work by almost doubling the number of reactions from 3565 to 6851. Over 70% of the reactions have been manually updated/revised in terms of reversibility, reactant pairs, currency metabolites and error correction. For the first time, 41 spontaneous sugar mutarotation reactions are introduced into the biochemical database. The upgrade significantly improves the reconstruction of genome scale metabolic networks. Many gaps or missing biochemical links can be recovered, as exemplified with three model organisms Homo sapiens, Aspergillus niger, and Escherichia coli. The topological parameters of the constructed networks were also largely affected, however, the overall network structure remains scale-free. Furthermore, we consider the problem of computing biologically feasible shortest paths in reconstructed metabolic networks. We show that these paths are hard to compute and present solutions to find such paths in networks of small and medium size