Search Results (31)

Background/Objectives: Municipal wastewater treatment plants (WWTPs) act as reservoirs for antibiotic-resistant bacteria, which pose a threat to global public health. In this study, we used whole-genome sequencing (WGS) to characterize antibiotic resistance genes (ARGs) and their association with mobile genetic elements (MGEs) in five multidrug-resistant (MDR) Escherichia coli isolates from dewatered sludge cake samples collected from a municipal WWTP in Cheongju, Republic of Korea. Methods: Susceptibility to nine antibiotics was evaluated via disk diffusion assay. Among the isolates exhibiting multidrug resistance (MDR) to three or more antibiotic classes, five isolates were randomly selected for whole-genome sequencing using the Illumina NovaSeqX platform. Additionally, we compared the genomic structures of five WWTP isolates with 35 environmental E. coli isolates from South Korea deposited in the NCBI pathogen database. ARGs and MGEs, including plasmids, integrons, and insertion sequences (ISs), were detected in the genome assemblies. Results: ARGs were differentially distributed between chromosomal and plasmid-derived contigs. Efflux pump-related genes were predominantly located on the chromosome across all isolates, whereas several beta-lactamase genes (e.g., bla_TEM-30 and bla_TEM-33), fluoroquinolone, and tetracycline resistance genes were localized on putative plasmid contigs. Furthermore, we characterized specific MGEs associated with these ARGs, including a class 1 integron gene cassette (dfrA17–aadA5–qacEΔ1–sul1) and an IS-mediated module (mph(A)–mrx–IS6100). Core-genome multilocus sequence typing (cgMLST) revealed that these MDR isolates represented diverse genetic lineages rather than a single clonal cluster. Conclusions: The results from this study highlight the necessity of enhanced post-treatment management of wastewater byproducts and WGS-based surveillance to mitigate the environmental spread of MDR bacteria. Full article

Background: RNA therapeutics represent a rapidly advancing field with significant potential for treating viral infections and cancer. This review examines the current landscape of RNA-based strategies, including siRNA, miRNA mimics, and antisense oligonucleotides. For viral infections, the focus is on hepatitis B (HBV) and C (HCV), HIV, and SARS-CoV-2. Approaches include targeting viral transcripts directly (e.g., siRNAs against HBV surface antigen) or host factors critical for viral replication (e.g., anti-miR-122 miravirsen for HCV). The successful development of mRNA vaccines for COVID-19 is highlighted as a major breakthrough, demonstrating the feasibility of rapid RNA vaccine deployment. The manuscript reviews several RNA therapeutics in oncology that have reached clinical trials. These include TargomiR (a miR-16 mimic for mesothelioma), cobomarsen (an anti-miR-155 for lymphomas), and MRX34 (a miR-34a mimic for various solid tumours). The review also covers emerging candidates like an miR-221 inhibitor and various strategies for breast cancer, such as targeting Bcl-2, KRAS, and specific miRNAs. A critical challenge across both fields is developing efficient and safe delivery systems, including lipid nanoparticles, GalNAc conjugates, and bacterial minicells. Despite promising preclinical results, clinical translation has been hampered by issues like insufficient delivery efficiency to human tumours, toxicity, and the complex, interconnected regulatory networks of miRNAs, which can lead to unpredictable off-target effects. Conclusions: While RNA therapeutics hold immense promise, overcoming delivery barriers and enhancing understanding of RNA regulatory networks are essential for future success. Full article

MicroRNAs (miRNAs) are ~19–25-nt post-transcriptional regulators whose dysregulation promotes hallmark cancer traits and therapy resistance. This review synthesizes translational principles for developing miRNA therapeutics in oncology, integrating miRNA biology and target engagement with delivery design and clinical experience. We summarize key determinants that shape efficacy and safety, including sequence and chemistry choices, biodistribution and intracellular delivery, dosing strategy, and biomarker-informed patient selection. We compare the main therapeutic modalities, miRNA mimics and inhibitors, and evaluate leading delivery approaches relevant to cancer, including lipid-based systems, polymer-based carriers and conjugates, and extracellular vesicle-inspired platforms, highlighting trade-offs in stability, specificity, immune activation, and tumor exposure. Early clinical programs such as MRX34, TargomiR/MesomiR-1, and cobomarsen, together with experience from non-oncology indications, illustrate both opportunities and practical constraints on tolerability and regimen optimization. We conclude with pragmatic priorities for the field, including standardized analytics for isoforms and target engagement, PK/PD- and biomarker-guided dose selection, and rational combination strategies to safely integrate miRNA-based interventions into precision oncology. Full article

Magnetic Relaxometry (MRX) is a promising technique for probing the magnetic properties of nanoparticles with considerable potential in biomedical applications. It magnetizes magnetic nanoparticles through a direct current magnetic field to obtain measurable Néel relaxation signals when magnetic nanoparticles are combined with specific cells or antibodies. It employs highly sensitive magnetic sensors to record relaxation signals following nanoparticle magnetization, from which intrinsic parameters and quantitative information can be extracted, and ultimately completes mass detection. The essential step in MRX-based mass detection is to establish the calibration relationship between the relaxation signal amplitude reflecting the magnetic moment and the corresponding mass of magnetic nanoparticles. In this article, we present a parameter estimation and quantification framework that integrates an improved Particle Swarm Optimization (PSO) algorithm with the Moment Superposition Model (MSM) as the objective function. The proposed method effectively combines experimental data with a theoretical model, enabling accurate determination of key intrinsic parameters, including saturation magnetization and magnetic anisotropy. Building on these reliable estimating parameters, the proposed PSO algorithm is further applied to quantify nanoparticle mass. Validation through simulations and experimental data confirms the robustness of the method, with the final mass detection error reaching the microgram level. These results highlight its potential for precise characterization of magnetic nanoparticles in biomedical contexts. Full article

Some recent published works have provided an exhaustive characterization of the plasma dynamics during magnetic reconnections in the presence of a magnetic guide field in MRX laboratory plasmas, including an assessment of the mechanisms that convert from magnetic energy to plasma kinetic energy. Among other results, the measurements indicate the existence of a correlation between the electron temperature and the generation of a spectrum of electric oscillations during the reconnection. In this work, we adapt to MRX conditions the well-known stochastic particle heating mechanism, frequently adopted in the astrophysical literature to justify ion heating by low-frequency large-amplitude electromagnetic waves. We show that, under MRX conditions. it may potentially provide a relevant contribution to electron energization. Full article

Outcomes are poor in patients with advanced or relapsed Ewing sarcoma (EWS) and current treatments have significant short- and long-term side effects. New, less toxic and more effective treatments are urgently needed. MER proto-oncogene tyrosine kinase (MERTK) promotes tumor cell survival, metastasis, and resistance to cytotoxic and targeted therapies in a variety of cancers. MERTK was ubiquitously expressed in five EWS cell lines and five patient samples. Moreover, data from CRISPR-based library screens indicated that EWS cell lines are particularly dependent on MERTK. Treatment with MRX-2843, a first-in-class, MERTK-selective tyrosine kinase inhibitor currently in clinical trials, decreased the phosphorylation of MERTK and downstream signaling in a dose-dependent manner in A673 and TC106 cells and provided potent anti-tumor activity against all five EWS cell lines, with IC₅₀ values ranging from 178 to 297 nM. Inhibition of MERTK correlated with anti-tumor activity, suggesting MERTK inhibition as a therapeutic mechanism of MRX-2843. Combined treatment with MRX-2843 and BCL-2 inhibitors venetoclax or navitoclax provided enhanced therapeutic activity compared to single agents. These data highlight MERTK as a promising therapeutic target in EWS and provide rationale for the development of MRX-2843 for the treatment of EWS, especially in combination with BCL-2 inhibitors. Full article

MRX-8 is a novel polymyxin for carbapenem-resistant Gram-negative infections that has been recently evaluated in Phase I clinical trials. Herein, its pharmacokinetics (PK) and nephrotoxicity in rats are reported for the first time. This study aimed at pre-clinical PK and safety assessments. An LC-MS/MS method was developed to determine concentrations of MRX-8 and its major deacylation metabolite, MRX-8039, in rat plasma. Animals were administered a single dose of MRX-8 (2, 4, 6, and 8 mg/kg) or comparator polymyxin B (PMB) (4 and 8 mg/kg) to compare the kidney injury known for the polymyxin drug class. Nephrotoxicity was evaluated using serum creatinine, blood urea nitrogen (BUN) biomarkers, and renal histopathology. In rats, MRX-8 displayed linear PK within the range of 2–8 mg/kg, with approximately 4% of MRX-8 converted to MRX-8039. MRX-8 induced only mild increases in serum creatinine and BUN levels, with an apparent decrease in nephrotoxicity within 24 h, in contrast to PMB, which exhibited a significant and more persistent toxicity. Additional nephrotoxicity biomarkers (plasma NGAL and urinary NGAL, KIM-1, and TIMP-1) have confirmed attenuated MRX-8 kidney injury. Histopathology has revealed significantly greater cellular/tissue toxicity for PMB as compared to MRX-8 (variances of p = 0.008 and p = 0.048 vs. saline control, respectively). Thus, MRX-8 induces a mild and reversible kidney injury in rats compared to PMB. These data support a continued evaluation of the novel polymyxin in human trials. Full article

The Water-Cooled Lead Lithium (WCLL) Breeding Blanket (BB) is one of the two BB concept candidates to be selected as the driver blanket for the EU DEMO fusion reactor. In this regard, the development of a sound architecture of the WCLL Central Outboard Blanket (COB) Segment, ensuring the fulfilment of the thermal and structural design requirements, is one of the main goals of the EUROfusion consortium. To this purpose, an exploratory research campaign has been launched to preliminarily investigate the thermo-mechanical performances of the Bottom Cap (BC) region of the WCLL COB segment because of its peculiarities making its design different from the other regions. The assessment has been carried out considering the nominal BB operating conditions, the Normal Operation (NO) scenario, as well as a steady-state scenario derived from the in-box LOCA accident, the Over-Pressurization (OP) scenario. Starting from the reference geometric layout of the WCLL COB BC region, a first set of analyses has been launched in order to evaluate its structural performances under a previously calculated thermal field and to select potential geometric improvements. Then, the analysis of a complete BC region was conducted from both the thermal and structural standpoints, evaluating its structural behaviour in compliance with the RCC-MRx code. Finally, after some iterations and geometric updates, a promising geometric layout of the BC region has been obtained even though some criticalities still persist in the internal Stiffening Plates and First Wall. However, the obtained results clearly showed that the proposed layout is worthy to be further assessed to achieve a robust enough configuration. The work has been performed following a theoretical-numerical approach based on the Finite Element Method (FEM) and adopting the quoted Ansys commercial FEM code. Full article

DNA double-strand breaks (DSBs) are a significant threat to cell viability due to the induction of genome instability and the potential loss of genetic information. One of the key players for early DNA damage response is the conserved Mre11/Rad50 Nbs1/Xrs2 (MRN/X) complex, which is quickly recruited to the DNA’s ruptured ends and is required for their tethering and their subsequent repair via different pathways. The MRN/X complex associates with several other proteins to exert its functions, but it also exploits sophisticated internal dynamic properties to orchestrate the several steps required to address the damage. In this review, we summarize the intrinsic molecular features of the MRN/X complex through biophysical, structural, and computational analyses in order to describe the conformational transitions that allow for this complex to accomplish its multiple functions. Full article

In the EU, the Water-Cooled Lithium Lead (WCLL) Breeding Blanket (BB) concept is one of the candidates for the design of the DEMO reactor. From the past campaign of analysis emerged that the thermal-induced stress led to the failure in the verification of the RCC-MRx structural criteria. Hence, in this paper the classic conceptual design approach, based on a pure FEM thermal and structural analysis, is compared to a coupled thermofluid-dynamic/structural one. Even though the coupled approach requires tremendous modelling effort and computational burden, it surely allows determining the thermal field with a higher level of detail than the FEM analysis. Therefore, in this work, the focus is put on the impact of a more detailed thermal field on the DEMO WCLL BB global structural performances, focusing on the Top Cap region of its Central Outboard Blanket segment. The obtained results have allowed confirming the soundness of the design solution of the Top Cap region, except for concerns arising on the mass flow rate distribution. Moreover, results have shown that, globally, the pure FEM approach allows for obtaining more conservative results than the coupled one. This is a positive outcome in sight of the follow-up of the DEMO WCLL BB design, as it will be still possible adopting the pure FEM approach to quickly down-select design alternatives, using the most onerous coupled approach to finalise the most promising. Full article

The international fusion materials irradiation facility-DEMO-oriented neutron source (IFMIF-DONES) is a facility that is designed under the framework of the EU fusion roadmap. It is going to be an essential irradiation facility for testing and qualifying candidate materials under severe irradiation conditions of a neutron field having an energy spectrum like the one present in a fusion power reactor. The material specimens are irradiated in a containment structure named the test cell (TC), which is part of the test systems (TS). The TC also houses a part of the other major system (lithium system, LS), which provides the liquid lithium for the reaction through a piping system. At a point, the lithium piping needs to exit the TS, but the primary safety boundary must be continuous around these penetrations. Therefore, a special barrier, called the test systems–lithium systems interface cell (TLIC), has been developed around the piping system to provide a safety-approved and remotely maintainable vacuum boundary envelope. In this paper, the integrated design development of the TLIC is described, consisting of the design development according to the RCC-MRx code, the remote-handling (RH) needs, and the procedures and safety-related special needs of the design. Full article

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL. The early T-precursor (ETP-ALL) subset is characterized by an immature T-cell phenotype, chemoresistance, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in half of T-ALLs, particularly those with an immature T-cell phenotype, suggesting a role in ETP-ALL. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is essential for ETP-ALL cell survival. Here, we show that MERTK and BCL-2 mRNA and protein are preferentially expressed in ETP-ALL patient samples. The dual MERTK/FLT3 inhibitor MRX-2843 decreased MERTK activation and downstream signaling, inhibited cell expansion, and induced cell death in ETP-ALL cell lines. Further, 54% (21/39) of primary T-ALL patient samples were sensitive to MERTK inhibition. Treatment with MRX-2843 significantly reduced leukemia burden and prolonged survival in cell-line-derived T-ALL and ETP-ALL xenograft models. In a patient-derived ETP-ALL xenograft model, treatment with MRX-2843 markedly reduced peripheral blood leukemia and spleen weight compared to vehicle-treated mice and prolonged survival. MRX-2843 also synergized with venetoclax to provide enhanced anti-leukemia activity in ETP-ALL cell cultures, with a dose ratio of 1:20 MRX-2843:venetoclax providing optimal synergy. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL and provide rationale for clinical development. MRX-2843 monotherapy is currently being tested in patients with relapsed leukemia (NCT04872478). Further, our data indicate that combined MERTK and BCL-2 inhibition may be particularly effective for treatment of ETP-ALL. Full article

Although new-generation antimicrobials, in particular β-lactam/β-lactamase inhibitors, have largely replaced polymyxins in carbapenem-resistant Gram-negative bacterial infections, polymyxins are still needed for carbapanem-resistant Acinetobacter baumannii infections and in settings where novel agents are not readily available. Despite their potent in vitro activity, the clinical utility of polymyxins is significantly limited by their pharmacokinetic properties and nephrotoxicity risk. There is significant interest, therefore, in developing next-generation polymyxins with activity against colistin-resistant strains and lower toxicity than existing polymyxins. In this review, we aim to present the antibacterial activity mechanisms, in vitro and in vivo efficacy data, and toxicity profiles of new-generation polymyxins, including SPR206, MRX-8, and QPX9003, as well as the general characteristics of old polymyxins. Considering the emergence of colistin-resistant strains particularly in endemic regions, the restoration of the antimicrobial activity of polymyxins via PBT2 is also described in this review. Full article

Progressive familial intrahepatic cholestasis (PFIC) is a debilitating disease manifest by severe cholestasis, intractable pruritus and growth delay that ultimately leads to liver failure or transplantation. Maralixibat (MRX) was recently approved for the treatment of cholestatic pruritus in patients with Alagille syndrome. The aim of this study was to determine whether specific changes in the composition of the serum bile acid metabolome could predict pruritus response to treatment. Serum BAs (sBA) and 7α-hydroxy-4-cholesten-3-one (7α-C4), a surrogate marker of BA synthesis, were monitored by ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry over 72 weeks in PFIC patients with mild to moderate non-truncating bile salt export pump (BSEP) mutations (n = 19) treated with MRX. The weekly itch reported outcome observer (ItchRO[Obs]) score measured pruritus severity. Linear mixed models (LMM) were applied to explore the effects of individual sBA profiles and their relationship to pruritus response. Changes in the composition of sBA correlated with pruritus improvement. Notably, the trajectory of serum total and individual BA species and 7α-C4 were significantly associated with ItchRO[Obs] score (p < 0.05). These results reveal that beyond simple total sBA concentrations, specific changes to the BA metabolome are associated with pruritus reduction in patients with BSEP deficiency, thus providing further insight into causal relationship of bile acids and pruritus. Full article

NONO (Non-Pou Domain-Containing Octamer-Binding Protein) gene maps on chromosome Xq13.1 and hemizygous loss-of-function nucleotide variants are associated with an emerging syndromic form of intellectual developmental disorder (MRXS34; MIM #300967), characterized by developmental delay, intellectual disability, poor language, dysmorphic facial features, and microcephaly. Structural brain malformation, such as corpus callosum and cerebellar abnormalities, and heart defects, in particular left ventricular non-compaction (LVNC), represent the most recurrent congenital malformations, recorded both in about 80% of patients, and can be considered the distinctive imaging findings of this disorder. We present on a further case of NONO-related disease; prenatally diagnosed in a fetus with complete corpus callosum agenesis; absence of septum pellucidum; pericallosal artery; LVNC and Ebstein’s anomaly. A high-resolution microarray analysis demonstrated the presence of a deletion affecting the NONO 3′UTR; leading to a marked hypoexpression of the gene and the complete absence of the protein in cultured amniocytes. This case expands the mutational spectrum of MRXS34, advises to evaluate NONO variants in pre- and postnatal diagnosis of subjects affected by LVNC and other heart defects, especially if associated with corpus callosum anomalies and confirm that CNVs (Copy Number Variants) represent a non-negligible cause of Mendelian disorders. Full article