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.

The influence of serum uric acid on coronary atherosclerosis plaque phenotypes by computed tomography angiography: The missing link?

Background And Aims: The interaction of serum uric acid (SUA) with atherogenesis is incompletely understood. Aim of our study was to investigate the association of SUA levels with coronary plaque composition including high-risk-plaque (HRP) features by coronary computed tomography angiography (CTA) and for the prediction of major adverse cardiac events (MACE).

Methods And Results: 1242 patients (age 66.

Towards Novel Antiplasmodial Agents-Design, Synthesis and Antimalarial Activity of Second-Generation β-Carboline/Chloroquine Hybrids.

As the resistance of to the existing antimalarials increases, there is a crucial need to expand the antimalarial drug pipeline. We recently identified potent antimalarial compounds, namely harmiquins, hybrids derived from the β-carboline alkaloid harmine and 4-amino-7-chloroquinoline, a key structural motif of chloroquine (CQ). To further explore the structure-activity relationship, we synthesised 13 novel hybrid compounds at the position -9 of the β-carboline ring and evaluated their efficacy in vitro against 3D7 and Dd2 strains (CQ sensitive and multi-drug resistant, respectively).

Diagnostic Impact of Subcutaneous Edema in Gouty Feet Detected by Dual-Energy Computed Tomography and Ultrasound.

: The objective of our study was to evaluate the association and frequency of subcutaneous lymphedema in patients with gout primarily affecting the feet. : In 79 patients with acute gout, ultrasound (US) and dual-energy computed tomography (DECT) were performed to assess the presence of subcutaneous edema and extra- and intra-articular gouty deposits. In addition, the diagnostic utility of two post-processing DECT protocols were evaluated, comprising different minimum attenuation thresholds of 150 HU (DECT 150 protocol) and 120 HU (DECT 120 protocol), with the same maximum attenuation threshold (500 HU) and constant kilovoltage setting of tubes A and B at 80 and 140 kVp.

TKK130 is a 3-Hydroxy-Propanamidine (HPA) with Potent Antimalarial Activity and a High Barrier to Resistance.

Malaria continues to pose a significant burden on populations in endemic areas and requires innovative treatment options. Here, we report the synthesis and preclinical evaluation of the novel 3-hydroxypropanamidine (HPA) , which shows excellent antiplasmodial activity against drug-sensitive and -resistant strains. Moreover, in various human cell lines, the compound shows no cytotoxicity and excellent parasite selectivity.

Automated total nucleic acid extraction with magnetic beads for the detection of Plasmodium falciparum in large study cohorts.

Background: Molecular methods play an important role in clinical trials assessing anti-malarial drugs and vaccines, as well as in epidemiological studies aimed at detecting Plasmodium species, especially when dealing with large sample sizes. Molecular techniques are more sensitive and generally have a higher throughput compared to the gold standard microscopy. Further optimization can be achieved with automation of nucleic acid isolation, allowing for rapid and precise extraction.

Multicomponent syntheses enable the discovery of novel quisinostat-derived chemotypes as histone deacetylase inhibitors.

In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. First, the compounds were evaluated for their activity against the Plasmodium falciparum strains 3D7 and Dd2, the main malaria-causing parasite, identifying compound 18b of the type C series as the most potent.

Targeting the IspE Enzyme.

The enzyme IspE in is considered an attractive drug target, as it is essential for parasite survival and is absent in the human proteome. Yet it still has not been addressed by a small-molecule inhibitor. In this study, we conducted a high-throughput screening campaign against the IspE enzyme.

A comparison of isolated limb infusion/perfusion, immune checkpoint inhibitors, and intralesional therapy as first-line treatment for patients with melanoma in-transit metastases.

Background: Isolated limb infusion and perfusion (ILI/ILP) has been a mainstay treatment for unresectable melanoma in-transit metastases (ITM), but increased use of immune checkpoint inhibitors (ICI) and intralesional therapy (talimogene laherparepvec [TVEC]) introduced several different management options. This study compares first-line ILI/ILP, ICI, and TVEC.

Methods: Retrospective review from 12 international institutions included patients treated from 1990 to 2022 with first-line ILI/ILP, ICI, or TVEC for unresectable melanoma ITM.

[Small renal mass: which criteria are decisive for a tumor board?].

Small renal masses (SRM) are a heterogeneous group of tumors with varying metastatic potential. The increasing use and improvement in the quality of abdominal imaging have led to an increasingly earlier diagnosis of incidental SRM, which are asymptomatic and confined to the organ. Despite these advances in imaging and the growing use of renal tumor biopsies, preoperative diagnosis of malignancy remains difficult.

Serum antigen tests for the diagnosis of invasive aspergillosis: a retrospective comparison of five antigen assays and one beta-D-glucan assay.

Invasive aspergillosis (IA) is a life-threatening infection. Early and specific diagnosis is pivotal to ensure adequate therapy. Antigen testing from blood is a widespread and convenient diagnostic approach.

Tumour evolution and microenvironment interactions in 2D and 3D space.

To study the spatial interactions among cancer and non-cancer cells, we here examined a cohort of 131 tumour sections from 78 cases across 6 cancer types by Visium spatial transcriptomics (ST). This was combined with 48 matched single-nucleus RNA sequencing samples and 22 matched co-detection by indexing (CODEX) samples. To describe tumour structures and habitats, we defined 'tumour microregions' as spatially distinct cancer cell clusters separated by stromal components.

Evolution of Pfdhps and Pfdhfr mutations before and after adopting seasonal malaria chemoprevention in Nanoro, Burkina Faso.

Seasonal Malaria Chemoprevention consisting of monthly administration of amodiaquine/sulfadoxine-pyrimethamine to children aged 3-59 months during the transmission season could promote SP-resistance. Mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes were assessed before and after SMC adoption in Burkina Faso. A total of 769 dried blood spots were selected from studies conducted in Nanoro, Burkina Faso, between 2010 and 2020.

A viable hypomorphic mutation in the mitochondrial ribosome subunit, MRPS-31, exhibits mitochondrial dysfunction in .

The mitochondrial ribosome (mitoribosome) translates mitochondrial genome encoded proteins essential for cellular energy production. Given this critical role, defects in the mitoribosome can cause mitochondrial stress and manifest as multisystemic diseases. In a screen for unique activators of the mitochondrial unfolded protein response (UPR ) in , we recovered a strain harboring a missense mutation in the gene encoding mitochondrial ribosome protein S31 ( MRPS-31 )-a component of the mitoribosome small subunit.

Multiple distinct evolutionary mechanisms govern the dynamics of selfish mitochondrial genomes in Caenorhabditis elegans.

Cells possess multiple mitochondrial DNA (mtDNA) copies, which undergo semi-autonomous replication and stochastic inheritance. This enables mutant mtDNA variants to arise and selfishly compete with cooperative (wildtype) mtDNA. Selfish mitochondrial genomes are subject to selection at different levels: they compete against wildtype mtDNA directly within hosts and indirectly through organism-level selection.

The association between dexterity and upper limb impairment during stroke recovery.

Introduction: Stroke-induced upper limb disabilities can be characterized by both motor impairments and activity limitations, commonly assessed using Fugl-Meyer Motor Assessment for Upper Extremity (FMMA-UE) and Action Research Arm Test (ARAT), respectively. The relationship between the two assessments during recovery is largely unstudied. Expectedly they diverge over time when recovery of impairment (restitution) plateaus, but compensation-driven improvements still occur.

Development of peptoid-based heteroaryl-decorated histone deacetylase (HDAC) inhibitors with dual-stage antiplasmodial activity.

Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum, the deadliest malaria parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction.

High prevalence of the recently identified clonal lineage ST1299/CT3109 among vancomycin-resistant strains isolated from municipal wastewater.

Previously, we demonstrated that the majority of vancomycin-resistant (VREfm) strains from in-patients of the University Hospital Erlangen, Germany, belonged to only three clonal lineages, namely ST117/CT71 and two novel ST1299 lineages classified as CT3109 and CT1903. The goal of the current study was (i) to investigate whether VREfm is also detectable in wastewater of the city of Erlangen, (ii) to identify their molecular features, and (iii) to clarify whether VREfm could arise from the community of the city of Erlangen or can be (directly) connected to nosocomial infections in the hospital setting. From April to May 2023, a total of 244 VREfm strains from raw wastewater of the city of Erlangen were analyzed by core genome multilocus sequence typing (cgMLST).

The Aspergillus galactomannan Ag VIRCLIA® Monotest and the sõna Aspergillus galactomannan lateral flow assay show comparable performance for the diagnosis of invasive aspergillosis.

Background: Rapid galactomannan tests, such as the sõna Aspergillus GM Lateral Flow Assay (GM-LFA) and the Aspergillus Galactomannan Ag VIRCLIA® Monotest (GM-Monotest), which are suitable for the analysis of single samples, have the potential to accelerate diagnosis of invasive aspergillosis (IA).

Objectives: To compare the performance of the GM-Monotest and the GM-LFA for the diagnosis of IA.

Patients/methods: Two patient cohorts were analysed: adults who had received an allogeneic haematopoietic stem-cell transplant (alloHSCT-cohort) and patients with proven/probable IA from a 5-year period (cross-sectional IA-cohort).

Genetic diversity of in sub-Saharan Africa: a two-marker genotyping approach for molecular epidemiological studies.

Introduction: is the most common non-falciparum species in sub-Saharan Africa. Despite this, data on its genetic diversity is scarce. Therefore, we aimed to establish a genotyping approach based on size polymorphic regions that can be easily applied in molecular epidemiological studies.

Design, Synthesis, Antitumor, and Antiplasmodial Evaluation of New 7-Chloroquinoline-Benzimidazole Hybrids.

Newly synthesized 7-chloro-4-aminoquinoline-benzimidazole hybrids were characterized by NMR and elemental analysis. Compounds were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts) and carcinoma (HeLa and CaCo-2), leukemia, and lymphoma (Hut78, THP-1, and HL-60) cell lines. The obtained results, expressed as the concentration at which 50% inhibition of cell growth is achieved (IC value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC ranged from 0.

PEMOCS: Evaluating the effects of a concept-guided, PErsonalised, MOtor-Cognitive exergame training on cognitive functions and gait in chronic Stroke-study protocol for a randomised controlled trial.

Background: Many stroke survivors remain with residual cognitive and motor impairments despite receiving timely acute and sub-acute rehabilitation. This indicates that rehabilitation following stroke should be continuous to meet the needs of individual stroke patients. Both cognitive and motor functions are essential for mastering daily life and, therefore, should be aimed at with rehabilitation.

Ex vivo study on the human blood neutrophil circadian features and effects of alpha1-antitrypsin and lipopolysaccharide.

Aims: Neutrophils perform various functions in a circadian-dependent manner; therefore, we investigated here whether the effect of alpha1-antitrypsin (AAT), used as augmentation therapy, is dependent on the neutrophil circadian clock. AAT is a vital regulator of neutrophil functions, and its qualitative and/or quantitative defects have significant implications for the development of respiratory diseases.

Methods: Whole blood from 12 healthy women age years, mean (SD) 29.