The NOAH HSQC-COSY module revisited: A theoretical and practical comparison of pulse sequences.

NMR supersequences, as exemplified by the NOAH (NMR by Ordered Acquisition using H detection) technique, are a powerful way of acquiring multiple 2D data sets in much shorter durations. This is accomplished through targeted excitation and detection of the magnetisation belonging to specific isotopologues ('magnetisation pools'). Separately, the HSQC-COSY experiment has recently seen an increase in popularity due to the high signal dispersion in the indirect dimension and the removal of ambiguity traditionally associated with HSQC-TOCSY experiments.

Bimolecular Sandwich Aggregates of Porphyrin Nanorings.

Extended π-systems often form supramolecular aggregates, drastically changing their optical and electronic properties. However, aggregation processes can be difficult to characterize or predict. Here, we show that butadiyne-linked 8- and 12-porphyrin nanorings form stable and well-defined bimolecular aggregates with remarkably sharp NMR spectra, despite their dynamic structures and high molecular weights (12.

How Clavulanic Acid Inhibits Serine β-Lactamases.

Clavulanic acid is a medicinally important inhibitor of serine β-lactamases (SBLs). We report studies on the mechanisms by which clavulanic acid inhibits representative Ambler class A (TEM-116), C (Escherichia coli AmpC), and D (OXA-10) SBLs using denaturing and non-denaturing mass spectrometry (MS). Similarly to observations with penam sulfones, most of the results support a mechanism involving acyl enzyme complex formation, followed by oxazolidine ring opening without efficient subsequent scaffold fragmentation (at pH 7.

Rhodanine derived enethiols react to give 1,3-dithiolanes and mixed disulfides.

Rhodanines have been characterised as 'difficult to progress' compounds for medicinal use, though one rhodanine is used for diabetes mellitus treatment and others are in clinical development. Rhodanines can undergo hydrolysis to enethiols which are inhibitors of metallo-enzymes, such as metallo β-lactamases. We report that in DMSO, rhodanine derived enethiols undergo dimerisations to give 1,3-dithiolanes and mixed disulfides.

Ex-Vivo C NMR Spectroscopy of Rodent Brain: TNF Restricts Neuronal Utilization of Astrocyte-Derived Metabolites.

Tumor necrosis factor (TNF) has well-established roles in neuroinflammatory disorders, but the effect of TNF on the biochemistry of brain cells remains poorly understood. Here, we microinjected TNF into the brain to study its impact on glial and neuronal metabolism (glycolysis, pentose phosphate pathway, citric acid cycle, pyruvate dehydrogenase, and pyruvate carboxylase pathways) using C NMR spectroscopy on brain extracts following intravenous [1,2-C]-glucose (to probe glia and neuron metabolism), [2-C]-acetate (probing astrocyte-specific metabolites), or [3-C]-lactate. An increase in [4,5-C]-glutamine and [2,3-C]-lactate coupled with a decrease in [4,5-C]-glutamate was observed in the [1,2-C]-glucose-infused animals treated with TNF.

Cyclic peptides target the aromatic cage of a PHD-finger reader domain to modulate epigenetic protein function.

Plant homeodomain fingers (PHD-fingers) are a family of reader domains that can recruit epigenetic proteins to specific histone modification sites. Many PHD-fingers recognise methylated lysines on histone tails and play crucial roles in transcriptional regulation, with their dysregulation linked to various human diseases. Despite their biological importance, chemical inhibitors for targeting PHD-fingers are very limited.

A general scheme for generating NMR supersequences combining high- and low-sensitivity experiments.

NOAH supersequences are a way of collecting multiple 2D NMR experiments in a single measurement. So far, this approach has been limited to experiments with comparable sensitivity. Here, we propose a scheme which overcomes this limitation, combining experiments with very different sensitivities such as 1,1-ADEQUATE, N HMBC, and C HSQC.

Corrigendum: Determination of CSF GFAP, CCN5, and vWF levels enhances the diagnostic accuracy of clinically defined MS from non-MS patients with CSF oligoclonal bands.

[This corrects the article DOI: 10.3389/fimmu.2021.

Bending a photonic wire into a ring.

Natural light-harvesting systems absorb sunlight and transfer its energy to the reaction centre, where it is used for photosynthesis. Synthetic chromophore arrays provide useful models for understanding energy migration in these systems. Research has focused on mimicking rings of chlorophyll molecules found in purple bacteria, known as 'light-harvesting system 2'.

Metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal model.

Background: Despite widespread searches, there are currently no validated biofluid markers for the detection of subclinical neuroinflammation in multiple sclerosis (MS). The dynamic nature of human metabolism in response to changes in homeostasis, as measured by metabolomics, may allow early identification of clinically silent neuroinflammation. Using the delayed-type hypersensitivity (DTH) MS rat model, we investigated the serum and cerebrospinal fluid (CSF) metabolomics profiles and neurofilament-light chain (NfL) levels, as a putative marker of neuroaxonal damage, arising from focal, clinically silent neuroinflammatory brain lesions and their discriminatory abilities to distinguish DTH animals from controls.

Counterion-Mediated Enantioconvergent Synthesis of Axially Chiral Medium Rings.

There are few enantioconvergent reactions in which racemic substrates bearing multiple stereochemical features are converted into products with high levels of diastereo- and enantiocontrol. Here, we disclose a process for the highly enantio- and diastereoselective syntheses of medium ring lactams via an intramolecular counterion-directed -alkylation reaction. The treatment of racemic biaryl anilides that exist as a complex mixture of enantiomers and diastereoisomeric conformers by virtue of multiple axes of restricted rotation with a quinidine-derived ammonium salt under basic conditions affords medium ring lactams bearing elements of both axial and point chirality via an enolate-driven configurational relaxation process.

Spectroscopic studies reveal details of substrate-induced conformational changes distant from the active site in isopenicillin N synthase.

Isopenicillin N synthase (IPNS) catalyzes formation of the β-lactam and thiazolidine rings of isopenicillin N from its linear tripeptide l-δ-(α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) substrate in an iron- and dioxygen (O)-dependent four-electron oxidation without precedent in current synthetic chemistry. Recent X-ray free-electron laser studies including time-resolved serial femtosecond crystallography show that binding of O to the IPNS-Fe(II)-ACV complex induces unexpected conformational changes in α-helices on the surface of IPNS, in particular in α3 and α10. However, how substrate binding leads to conformational changes away from the active site is unknown.

Pathogen-sugar interactions revealed by universal saturation transfer analysis.

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions.

In vivo antihyperglycaemic and antihyperlipidemic activities and chemical constituents of Solanum anomalum.

Solanum anomalum is a plant used ethnomedically for the treatment of diabetes. The study was aimed to validate ethnomedical claims in rat model and identify the likely antidiabetic compounds. Leaf extract (70-210 mg/kg/day) and fractions (140 mg/kg/day) of S.

Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study.

Asymmetric catalytic azidation has increased in importance to access enantioenriched nitrogen containing molecules, but methods that employ inexpensive sodium azide remain scarce. This encouraged us to undertake a detailed study on the application of hydrogen bonding phase-transfer catalysis (HB-PTC) to enantioselective azidation with sodium azide. So far, this phase-transfer manifold has been applied exclusively to insoluble metal alkali fluorides for carbon-fluorine bond formation.

Determination of CSF GFAP, CCN5, and vWF Levels Enhances the Diagnostic Accuracy of Clinically Defined MS From Non-MS Patients With CSF Oligoclonal Bands.

Background: Inclusion of cerebrospinal fluid (CSF) oligoclonal IgG bands (OCGB) in the revised McDonald criteria increases the sensitivity of diagnosis when dissemination in time (DIT) cannot be proven. While OCGB negative patients are unlikely to develop clinically definite (CD) MS, OCGB positivity may lead to an erroneous diagnosis in conditions that present similarly, such as neuromyelitis optica spectrum disorders (NMOSD) or neurosarcoidosis.

Objective: To identify specific, OCGB-complementary, biomarkers to improve diagnostic accuracy in OCGB positive patients.

Modular Pulse Program Generation for NMR Supersequences.

NMR supersequences allow multiple 2D NMR data sets to be acquired in greatly reduced experiment durations through tailored detection of NMR responses within concatenated modules. In NOAH (NMR by Ordered Acquisition using H detection) experiments, up to five modules can be combined (or even more when parallel modules are employed), which in theory leads to thousands of plausible supersequences. However, constructing a pulse program for a supersequence is highly time-consuming, requires specialized knowledge, and is error-prone due to its complexity; this has prevented the true potential of the NOAH concept from being fully realized.

Polyyne [3]Rotaxanes: Synthesis via Dicobalt Carbonyl Complexes and Enhanced Stability.

New strategies for synthesizing polyyne polyrotaxanes are being developed as an approach to stable carbyne "insulated molecular wires". Here we report an active metal template route to polyyne [3]rotaxanes, using dicobalt carbonyl masked alkyne equivalents. We synthesized two [3]rotaxanes, both with the same C polyyne dumbbell component, one with a phenanthroline-based macrocycle and one using a 2,6-pyridyl cycloparaphenylene nanohoop.

Metabolomic Biomarkers in Blood Samples Identify Cancers in a Mixed Population of Patients with Nonspecific Symptoms.

Purpose: Early diagnosis of cancer is critical for improving patient outcomes, but cancers may be hard to diagnose if patients present with nonspecific signs and symptoms. We have previously shown that nuclear magnetic resonance (NMR) metabolomics analysis can detect cancer in animal models and distinguish between differing metastatic disease burdens. Here, we hypothesized that biomarkers within the blood metabolome could identify cancers within a mixed population of patients referred from primary care with nonspecific symptoms, the so-called "low-risk, but not no-risk" patient group, as well as distinguishing between those with and without metastatic disease.

Parallel NMR Supersequences: Ten Spectra in a Single Measurement.

The principles employed in parallel NMR and MRI are applied to NMR supersequences yielding as many as ten 2D NMR spectra in one measurement. We present a number of examples where two NOAH (NMR by Ordered Acquisition using H-detection) supersequences are recorded in parallel, thus dramatically increasing the information content obtained in a single NMR experiment. The two parallel supersequences entangled by time-sharing schemes (IPAP-seHSQC, HSQC-COSY, and HSQC-TOCSY) incorporate also modified (sequential and/or interleaved) conventional pulse schemes (modules), including HMBC, TOCSY, COSY, CLIP-COSY, NOESY, and ROESY.

Objective biomarkers for clinical relapse in multiple sclerosis: a metabolomics approach.

Accurate determination of relapses in multiple sclerosis is important for diagnosis, classification of clinical course and therapeutic decision making. The identification of biofluid markers for multiple sclerosis relapses would add to our current diagnostic armamentarium and increase our understanding of the biology underlying the clinical expression of inflammation in multiple sclerosis. However, there is presently no biofluid marker capable of objectively determining multiple sclerosis relapses although some, in particular neurofilament-light chain, have shown promise.

Characterisation of factors contributing to the performance of nonwoven fibrous matrices as substrates for adenovirus vectored vaccine stabilisation.

Adenovirus vectors offer a platform technology for vaccine development. The value of the platform has been proven during the COVID-19 pandemic. Although good stability at 2-8 °C is an advantage of the platform, non-cold-chain distribution would have substantial advantages, in particular in low-income countries.