Expanding the Chemical Space of Reverse Fosmidomycin Analogs.

Multidrug-resistant pathogens pose a major threat to human health, necessitating the identification of new drug targets and lead compounds that are not susceptible to cross-resistance. This study demonstrates that novel reverse thia analogs of the phosphonohydroxamic acid antibiotic fosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme for , , and that is absent in humans. Some novel analogs with large α-phenyl substituents exhibited strong inhibition across these three DXR orthologues, surpassing the inhibitory activity of fosmidomycin.

Adaptive Laboratory Evolution of Flavin Functionality Identifies Dihydrolipoyl Dehydrogenase as One of the Critical Points for the Activity of 7,8-Didemethyl-Riboflavin as a Surrogate for Riboflavin in .

Riboflavin analogs lacking one methyl group (7α or 8α) can still serve as a surrogate for riboflavin in riboflavin-deficient microorganisms or animals. The absence of both methyl groups at once completely abolishes this substitution capability. To elucidate the molecular mechanisms behind this phenomenon, we performed an adaptive laboratory evolution experiment (in triplicate) on an strain auxotrophic for riboflavin.

Comparative Influences of Beta blockers and Verapamil on Cardiac Outcomes in Hypertrophic Cardiomyopathy.

Guidelines recommend β blockers (BBs) as first-line therapy in symptomatic patients with hypertrophic cardiomyopathy (HCM) and nondihydropyridine calcium channel blockers, particularly, verapamil, as the second-line therapy, despite the absence of comparison trials between those 2 drugs. Because deleterious effects of verapamil have been reported in this setting, the present analysis aimed to evaluate the prognostic impact of BBs and verapamil in a cohort of patients with HCM. From a nationwide cohort of 1,434 patients with a diagnosis of HCM included in the French prospective observational REgistry of hypertrophic cardioMYopathy (REMY), we retrospectively analyzed patients with sarcomeric HCM included in the 3 largest centers and treated either with BBs or verapamil.

The French hypertrophic cardiomyopathy gene register: A systematic large gene screening for hypertrophic cardiomyopathy.

Background: Although the optimal approach is debated, systematic genetic screening for hypertrophic cardiomyopathy (HCM) is recommended.

Aims: The performance of this approach was tested in GEREMY, a HCM prospective observational French register.

Methods: Screening was based on a 12-gene panel, including the Fabry disease (GLA) and the transthyretin (TTR) genes.

Target population for a selective cardiac myosin inhibitor in hypertrophic obstructive cardiomyopathy: Real-life estimation from the French register of hypertrophic cardiomyopathy (REMY).

Background: The efficacy of current pharmacological therapies in hypertrophic cardiomyopathy is limited. A cardiac myosin inhibitor, mavacamten, has recently been approved as a first-in-class treatment for symptomatic hypertrophic obstructive cardiomyopathy.

Aims: To assess the profile and burden of cardiac myosin inhibitor candidates in the hypertrophic cardiomyopathy prospective Register of hypertrophic cardiomyopathy (REMY) held by the French Society of Cardiology.

First-in-man use of a cardiovascular cell-derived secretome in heart failure. Case report.

Background: There is increased evidence that the effects of stem cells can mostly be duplicated by administration of their secretome which might streamline the translation towards the clinics.

Methods: The 12-patient SECRET-HF phase 1 trial has thus been designed to determine the feasibility and safety of repeated intravenous injections of the extracellular vesicle (EV)-enriched secretome of cardiovascular progenitor cells differentiated from pluripotent stem cells in severely symptomatic patients with drug-refractory left ventricular (LV) dysfunction secondary to non-ischemic dilated cardiomyopathy. Here we report the case of the first treated patient (baseline NYHA class III; LV Ejection Fraction:25%) in whom a dose of 20 × 10 particles/kg was intravenously infused three times three weeks apart.

Reverse -Substituted Hydroxamic Acid Derivatives of Fosmidomycin Target a Previously Unknown Subpocket of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR).

Reverse analogs of the phosphonohydroxamic acid antibiotic fosmidomycin are potent inhibitors of the nonmevalonate isoprenoid biosynthesis enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR, IspC) of . Some novel analogs with large phenylalkyl substituents at the hydroxamic acid nitrogen exhibit nanomolar DXR inhibition and potent growth inhibition of parasites coupled with good parasite selectivity. X-ray crystallographic studies demonstrated that the -phenylpropyl substituent of the newly developed lead compound is accommodated in a subpocket within the DXR catalytic domain but does not reach the NADPH binding pocket of the -terminal domain.

Systematic Analysis of the Effect of Genomic Knock-Out of Non-Essential Promiscuous HAD-Like Phosphatases YcsE, YitU and YwtE on Flavin and Adenylate Content in Bacillus Subtilis.

Studying the metabolic role of non-essential promiscuous enzymes is a challenging task, as genetic manipulations usually do not reveal at which point(s) of the metabolic network the enzymatic activity of such protein is beneficial for the organism. Each of the HAD-like phosphatases YcsE, YitU and YwtE of Bacillus subtilis catalyzes the dephosphorylation of 5-amino-6-ribitylamino-uracil 5'-phosphate, which is essential in the biosynthesis of riboflavin. Using CRISPR technology, we have found that the deletion of these genes, individually or in all possible combinations failed to cause riboflavin auxotrophy and did not result in significant growth changes.

Elucidating the Signal Transduction Mechanism of the Blue-Light-Regulated Photoreceptor YtvA: From Photoactivation to Downstream Regulation.

The blue-light photoreceptor YtvA from has an N-terminal flavin mononucleotide (FMN)-binding light-oxygen-voltage (LOV) domain that is fused to a C-terminal sulfate transporter and anti-σ factor antagonist (STAS) output domain. To interrogate the signal transduction pathway that leads to photoactivation, the STAS domain was replaced with a histidine kinase, so that photoexcitation of the flavin could be directly correlated with biological activity. N94, a conserved Asn that is hydrogen bonded to the FMN C2═O group, was replaced with Ala, Asp, and Ser residues to explore the role of this residue in triggering the structural dynamics that activate the output domain.

Shining a Spotlight on Methyl Groups: Photochemically Induced Dynamic Nuclear Polarization Spectroscopy of 5-Deazariboflavin and Its Nor Analogs.

5-Deazaflavins are analogs of naturally occurring flavin cofactors. They serve as substitutes for natural flavin cofactors to investigate and modify the reaction pathways of flavoproteins. Demethylated 5-deazaflavins are potential candidates for artificial cofactors, allowing us to fine-tune the reaction kinetics and absorption characteristics of flavoproteins.

Expanding Reaction Horizons: Evidence of the 5-Deazaflavin Radical Through Photochemically Induced Dynamic Nuclear Polarization.

Deazaflavins are important analogues of the naturally occurring flavins: riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD). The use of 5-deazaflavin as a replacement coenzyme in a number of flavoproteins has proven particularly valuable in unraveling and manipulating their reaction mechanisms. It was frequently reported that one-electron-transfer reactions in flavoproteins are impeded with 5-deazaflavin as the cofactor.

Radial Alignment of Carbon Nanotubes via Dead-End Filtration.

Dead-end filtration is a facile method to globally align single wall carbon nanotubes (SWCNTs) in large area films with a 2D order parameter, S , approaching unity. Uniaxial alignment has been achieved using pristine and hot-embossed membranes but more sophisticated geometries have yet to be investigated. In this work, three different patterns with radial symmetry and an area of 3.

The Impact of Carbon Nanotube Length and Diameter on their Global Alignment by Dead-End Filtration.

Dead-end filtration has proven to effectively prepare macroscopically (3.8 cm ) aligned thin films from solutionbased single-wall carbon nanotubes (SWCNTs). However, to make this technique broadly applicable, the role of SWCNT length and diameter must be understood.

Granular aluminium nanojunction fluxonium qubit.

Mesoscopic Josephson junctions, consisting of overlapping superconducting electrodes separated by a nanometre-thin oxide layer, provide a precious source of nonlinearity for superconducting quantum circuits. Here we show that in a fluxonium qubit, the role of the Josephson junction can also be played by a lithographically defined, self-structured granular aluminium nanojunction: a superconductor-insulator-superconductor Josephson junction obtained in a single-layer, zero-angle evaporation. The measured spectrum of the resulting qubit, which we nickname gralmonium, is indistinguishable from that of a standard fluxonium.

Completing the Picture: Determination of C Hyperfine Coupling Constants of Flavin Semiquinone Radicals by Photochemically Induced Dynamic Nuclear Polarization Spectroscopy.

We investigate the electronic structure of flavin semiquinone radicals in terms of their C hyperfine coupling constants. Photochemically induced dynamic nuclear polarization (photo-CIDNP) spectroscopy was used to study both the neutral and anionic radical species of flavin mononucleotide (FMN) in bulk aqueous solution. Apart from universally C-labeled FMN, partially labeled isotopologues are used to increase sensitivity for nuclei exhibiting very small hyperfine couplings and to cope with spectral overlap.

Clinical relevance of lung transplantation for COVID-19 ARDS: a nationwide study.

Background: Although the number of lung transplantations (LTx) performed worldwide for coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS) is still low, there is general agreement that this treatment can save a subgroup of the most severely ill patients with irreversible lung damage. However, the true proportion of patients eligible for LTx, the overall outcome and the impact of LTx on the pandemic are unknown.

Methods: A retrospective analysis was performed using a nationwide registry of hospitalised patients with confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection admitted between 1 January 2020 and 30 May 2021 in Austria.

Design Strategy for Nanostructured Arrays of Metallodielectric Cuboids to Systematically Tune the Optical Response and Eliminate Spurious Bulk Effects in Plasmonic Biosensors.

Plasmonic biosensors are a powerful tool for studying molecule adsorption label-free and with high sensitivity. Here, we present a systematic study on the optical properties of strictly regular nanostructures composed of metallodielectric cuboids with the aim to deliberately tune their optical response and improve their biosensing performance. In addition, the patterns were tested for their potential to eliminate spurious effects from sensor response, caused by refractive index changes in the bulk solution.

Selective C labelling reveals the electronic structure of flavocoenzyme radicals.

Flavocoenzymes are nearly ubiquitous cofactors that are involved in the catalysis and regulation of a wide range of biological processes including some light-induced ones, such as the photolyase-mediated DNA repair, magnetoreception of migratory birds, and the blue-light driven phototropism in plants. One of the factors that enable versatile flavin-coenzyme biochemistry and biophysics is the fine-tuning of the cofactor's frontier orbital by interactions with the protein environment. Probing the singly-occupied molecular orbital (SOMO) of the intermediate radical state of flavins is therefore a prerequisite for a thorough understanding of the diverse functions of the flavoprotein family.

Field-effect silicon-plasmonic photodetector for coherent T-wave reception.

Plasmonic internal photoemission detectors (PIPED) have recently been shown to combine compact footprint and high bandwidth with monolithic co-integration into silicon photonic circuits, thereby opening an attractive route towards optoelectronic generation and detection of waveforms in the sub-THz and THz frequency range, so-called T-waves. In this paper, we further expand the PIPED concept by introducing a metal-oxide-semiconductor (MOS) interface with an additional gate electrode that allows to control the carrier dynamics in the device and the degree of internal photoemission at the metal-semiconductor interfaces. We experimentally study the behavior of dedicated field-effect (FE-)PIPED test structures and develop a physical understanding of the underlying principles.

Non-classical disproportionation revealed by photo-chemically induced dynamic nuclear polarization NMR.

Photo-chemically induced dynamic nuclear polarization (photo-CIDNP) was used to observe the light-induced disproportionation reaction of 6,7,8-trimethyllumazine starting out from its triplet state to generate a pair of radicals comprising a one-electron reduced and a one-electron oxidized species. Our evidence is based on the measurement of two marker proton hyperfine couplings, (H(6)) and (H(8)), which we correlated to predictions from density functional theory. The ratio of these two hyperfine couplings is reversed in the oxidized and the reduced radical species.

Management and outcomes of hypertrophic cardiomyopathy in young adults.

Background: Management of young adults with hypertrophic cardiomyopathy (HCM) is challenging.

Aims: To evaluate the profile of young adults (16-25 years) with HCM included in the French prospective HCM registry.

Methods: Patients were compared according to occurrence of major adverse cardiac events (MACE), comprising sudden cardiac death (SCD) events (implantable cardioverter defibrillator [ICD] discharge, SCD, sustained ventricular tachycardia), atrial fibrillation/embolic stroke, heart failure hospitalisation and unexplained syncope, at a mean follow-up of 4.

The EXP pair-potential system. IV. Isotherms, isochores, and isomorphs in the two crystalline phases.

This paper studies numerically the solid phase of a system of particles interacting by the exponentially repulsive pair potential, which is a face-centered cubic (fcc) crystal at low densities and a body-centered cubic (bcc) crystal at higher densities [U. R. Pedersen et al.

Excited State Vibrations of Isotopically Labeled FMN Free and Bound to a Light-Oxygen-Voltage (LOV) Protein.

Flavoproteins are important blue light sensors in photobiology and play a key role in optogenetics. The characterization of their excited state structure and dynamics is thus an important objective. Here, we present a detailed study of excited state vibrational spectra of flavin mononucleotide (FMN), in solution and bound to the LOV-2 (Light-Oxygen-Voltage) domain of phototropin.