A genome-scale metabolic reconstruction provides insight into the metabolism of the thermophilic bacterium Rhodothermus marinus.

The thermophilic bacterium Rhodothermus marinus has mainly been studied for its thermostable enzymes. More recently, the potential of using the species as a cell factory and in biorefinery platforms has been explored, due to the elevated growth temperature, native production of compounds such as carotenoids and exopolysaccharides, the ability to grow on a wide range of carbon sources including polysaccharides, and available genetic tools. A comprehensive understanding of the metabolism of cell factories is important.

Correction: Virtual screening, identification and validation of small molecule GDP-mannose dehydrogenase inhibitors.

[This corrects the article DOI: 10.1039/D3CB00126A.].

Deciphering the Interplay: Thieno[2,3-]pyridine's Impact on Glycosphingolipid Expression, Cytotoxicity, Apoptosis, and Metabolomics in Ovarian Tumor Cell Lines.

Ovarian cancer is among the most prevalent causes of mortality among women. Despite improvements in diagnostic methods, non-specific symptoms and delayed gynecological exams can lead to late-stage ovarian tumor discovery. In this study, the effect of an anti-cancer compound, 3-amino--(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-]quinoline-2-carboxamide (Compound ), was examined.

Are the metal identity and stoichiometry of metal complexes important for colchicine site binding and inhibition of tubulin polymerization?

Quite recently we discovered that copper(II) complexes with isomeric morpholine-thiosemicarbazone hybrid ligands show good cytotoxicity in cancer cells and that the molecular target responsible for this activity might be tubulin. In order to obtain better lead drug candidates, we opted to exploit the power of coordination chemistry to (i) assemble structures with globular shape to better fit the colchicine pocket and (ii) vary the metal ion. We report the synthesis and full characterization of bis-ligand cobalt(III) and iron(III) complexes with 6-morpholinomethyl-2-formylpyridine 4-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL1), 6-morpholinomethyl-2-acetylpyridine 4-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL2), and 6-morpholinomethyl-2-formylpyridine 4-phenyl-3-thiosemicarbazone (HL3), and -ligand nickel(II), zinc(II) and palladium(II) complexes with HL1, namely [Co(HL)(L)](NO) (1), [Co(HL)(L)](NO) (2), [Co(HL)(L)](NO) (3), [Fe(L)]NO (4), [Fe(HL)(L)](NO) (5), [Ni(L)]Cl (6), [Zn(L)Cl] (7) and [Pd(HL)Cl]Cl (8).

Accessing Active Fragments for Drug Discovery Utilising Nitroreductase Biocatalysis.

Biocatalysis has played a limited role in the early stages of drug discovery. This is often attributed to the limited substrate scope of enzymes not affording access to vast areas of novel chemical space. Here, we have shown a promiscuous nitroreductase enzyme (NR-55) can be used to produce a panel of functionalised anilines from a diverse panel of aryl nitro starting materials.

Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.

Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling.

IMPROVE: a feature model to predict neoepitope immunogenicity through broad-scale validation of T-cell recognition.

Background: Mutation-derived neoantigens are critical targets for tumor rejection in cancer immunotherapy, and better tools for neoepitope identification and prediction are needed to improve neoepitope targeting strategies. Computational tools have enabled the identification of patient-specific neoantigen candidates from sequencing data, but limited data availability has hindered their capacity to predict which of the many neoepitopes will most likely give rise to T cell recognition.

Method: To address this, we make use of experimentally validated T cell recognition towards 17,500 neoepitope candidates, with 467 being T cell recognized, across 70 cancer patients undergoing immunotherapy.

Adolescents on psychotropic treatment displayed longer corrected QT intervals than unmedicated controls when they rose rapidly from the supine position.

Aim: Psychotropic medication can contribute to arrhythmia and identifying individuals at risk is crucial. This Swedish study compared the corrected QT (QTc) intervals of adolescents on psychotropic medication with unmedicated controls, when supine and after rising rapidly.

Methods: The study was carried out at Östersund County Hospital in March 2022 and February to March 2023.

New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling.

Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC values in the submicromolar range. Furthermore, methyl esters -, as well as their acid counterparts -, inhibited the phosphodiesterase activity of both TDP1 and TDP2.

New light on the HLA-DR immunopeptidomic landscape.

The set of peptides processed and presented by major histocompatibility complex class II molecules defines the immunopeptidome, and its characterization holds keys to understanding essential properties of the immune system. High-throughput mass spectrometry (MS) techniques enable interrogation of the diversity and complexity of the immunopeptidome at an unprecedented scale. Here, we analyzed a large set of MS immunopeptidomics data from 40 donors, 221 samples, covering 30 unique HLA-DR molecules.

What You See Is Not What You Get: Frontal Sinus Metastasis From the Renal Cell Carcinoma.

Metastatic neoplasms occurring in the nasal and paranasal sinuses are infrequent occurrences. In this study, we present one such case of a 61-year-old male patient with a known clear cell renal carcinoma presenting to us with signs and symptoms of acute sinusitis. The patient subsequently underwent CT and MRI examinations, which revealed a neoplastic mass in the right frontal sinus, which was surgically resected and was later confirmed histologically as a metastatic deposit from clear cell renal carcinoma.

Development of a rabbit model of Adenosine triphosphate-induced monocular retinal degeneration for optimization of retinal prostheses.

Optimization of retinal prostheses requires preclinical animal models that mimic features of human retinal disease, have appropriate eye sizes to accommodate implantable arrays, and provide options for unilateral degeneration so as to enable a contralateral, within-animal control eye. In absence of a suitable non-human primate model and shortcomings of our previous feline model generated through intravitreal injections of Adenosine Triphosphate (ATP), we aimed in the present study to develop an ATP induced degeneration model in the rabbit. Six normally sighted Dutch rabbits were monocularly blinded with this technique.

Virtual screening, identification and validation of small molecule GDP-mannose dehydrogenase inhibitors.

Upon undergoing mucoid conversion within the lungs of cystic fibrosis patients, the pathogenic bacterium synthesises copious quantities of the virulence factor and exopolysaccharide alginate. The enzyme guanosine diphosphate mannose dehydrogenase (GMD) catalyses the rate-limiting step and irreversible formation of the alginate sugar nucleotide building block, guanosine diphosphate mannuronic acid. Since there is no corresponding enzyme in humans, strategies that could prevent its mechanism of action could open a pathway for new and selective inhibitors to disrupt bacterial alginate production.

Phosphatidylcholine-Specific Phospholipase C as a Promising Drug Target.

Phosphatidylcholine-specific phospholipase C (PC-PLC) is an enzyme that catalyzes the formation of the important secondary messengers phosphocholine and diacylglycerol (DAG) from phosphatidylcholine. Although PC-PLC has been linked to the progression of many pathological conditions, including cancer, atherosclerosis, inflammation and neuronal cell death, studies of PC-PLC on the protein level have been somewhat neglected with relatively scarce data. To date, the human gene expressing PC-PLC has not yet been found, and the only protein structure of PC-PLC that has been solved was from (PC-PLC).

Indolo[2,3-]benzazocines and indolo[2,3-]benzazonines and their copper(II) complexes as microtubule destabilizing agents.

A series of four indolo[2,3-]benzazocines HL1-HL4 and two indolo[2,3-]benzazonines HL5 and HL6, as well as their respective copper(II) complexes 1-6, were synthesized and characterized by H and C NMR spectroscopy, ESI mass spectrometry, single crystal X-ray diffraction (SC-XRD) and combustion analysis (C, H, N). SC-XRD studies of precursors Vd, VIa·0.5MeOH, of ligands HL4 and HL6·DCM, and complexes 2·2DMF, 5·2DMF, 5'·iPrOH·MeOH provided insights into the energetically favored conformations of eight- and nine-membered heterocycles in the four-ring systems.

Measuring Retinal Vessel Diameter from Mouse Fluorescent Angiography Images.

It is important to study the development of retinal vasculature in retinopathies in which abnormal vessel growth can ultimately lead to vision loss. Mutations in the microphthalmia-associated transcription factor (Mitf) gene show hypopigmentation, microphthalmia, retinal degeneration, and in some cases, blindness. In vivo imaging of the mouse retina by noninvasive means is vital for eye research.

New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan.

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is an important enzyme in the DNA repair system. The ability of the enzyme to repair DNA damage induced by a topoisomerase 1 poison such as the anticancer drug topotecan makes TDP1 a promising target for complex antitumor therapy. In this work, a set of new 5-hydroxycoumarin derivatives containing monoterpene moieties was synthesized.

[Spontaneous retroperitoneal hemorrhage].

A 50-year old male presented to our emergency department with sudden abdominal pain. Upon arrival he was diaphoretic, pale and tachycardic. A CT showed retroperitoneal hemorrhage with suspected tumor at the left adrenal gland.

Loss of Müller cell glutamine synthetase immunoreactivity is associated with neuronal changes in late-stage retinal degeneration.

Introduction: A hallmark of photoreceptor degenerations is progressive, aberrant remodeling of the surviving retinal neurons and glia following photoreceptor loss. The exact relationship between neurons and glia remodeling in this late stage of retinal degeneration, however, is unclear. This study assessed this by examining Müller cell dysfunction via glutamine synthetase immunoreactivity and its spatial association with retinal neuron subpopulations through various cell markers.

Novel TDP1 Inhibitors: Disubstituted Thiazolidine-2,4-Diones Containing Monoterpene Moieties.

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy; the use of TDP1 inhibitors with a topoisomerase 1 poison such as topotecan is a potential combination therapy. In this work, a novel series of 3,5-disubstituted thiazolidine-2,4-diones was synthesized and tested against TDP1. The screening revealed some active compounds with IC values less than 5 μM.

Comparison of medication adherence to different oral anticoagulants: population-based cohort study.

Objective: Previous observational studies have yielded conflicting results on whether medication adherence differs between patients receiving warfarin and direct oral anticoagulants (DOACs). Importantly, no study has adequately accounted for warfarin dosing being continuously modified based on INR values while dosing of DOACs is fixed. We aimed to compare non-adherence between new users of apixaban, dabigatran, rivaroxaban and warfarin in a population-based cohort.

Comparison of the effectiveness and safety of direct oral anticoagulants: a nationwide propensity score-weighted study.

In the pivotal randomized controlled trials (RCTs) for patients with atrial fibrillation, direct oral anticoagulants (DOACs) had similar or even superior efficacy and safety compared with warfarin. However, RCTs comparing different DOACs are nonexistent and previous observational studies have yielded conflicting results. In this nationwide cohort study, rates of any stroke or systemic embolism (stroke/SE) and major bleeding were compared among new users of apixaban, dabigatran, and rivaroxaban with atrial fibrillation from 2014 to 2019.

Immunopeptidomic Analysis of BoLA-I and BoLA-DR Presented Peptides from Infected Cells.

The apicomplexan parasite Theileria parva is the causative agent of East Coast fever, usually a fatal disease for cattle, which is prevalent in large areas of eastern, central, and southern Africa. Protective immunity against T. parva is mediated by CD8+ T cells, with CD4+ T-cells thought to be important in facilitating the full maturation and development of the CD8+ T-cell response.