Search Results (311)

Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking. We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC₅₀ and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC₅₀). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient. In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment. A comparison with known RAS showed that S759A, located in the active site of nsp12, conferred the highest remdesivir resistance (106.1-fold increase in replication). Nsp12-RAS V166A/L, V792I, E796D or C799F, all adjacent to the active site, caused intermediate resistance (2.0- to 11.5-fold), whereas N198S, D484Y, or E802D, located farther from the active site, showed no resistance (≤2.0-fold). In conclusion, our classification system, correlating replication under remdesivir treatment with RAS location in nsp12, shows that most nsp12-RAS cause moderate resistance. Full article

The steep incline in the rising need for sustainable construction materials has marked the emerging trend of comprehensive research on utilizing waste glass powder (WGP) as a partial substitute for fine aggregates, such as cement, and coarse aggregates in concrete preparation. This review thoroughly examines WGP-incorporated concrete in terms of its mechanical and durability properties. It explores compressive, tensile, and flexural strength, as well as its resistance to freeze–thaw cycles, sulfate attack, and chloride ion penetration. The characteristic microstructure densification, strength development, and durability performance can be attributed to the pozzolanic activity of WGP that forms additional calcium silicate hydrate (C-S-H). The review also highlights the optimal replacement levels of WGP to balance mechanical performance and long-term stability while addressing potential challenges, such as alkali–silica reaction (ASR) and reduced workability at high replacement ratios. By consolidating recent research findings, this study highlights the feasibility of WGP as a sustainable supplementary cementitious material (SCM), promoting eco-friendly construction while mitigating environmental concerns associated with glass waste disposal. Full article

Background: Postmenopausal women face a higher risk of obesity and related chronic diseases. While lifestyle interventions improve cardiometabolic health and physical function, their effects on cognitive function remain understudied, especially in diverse populations. This study examined the impact of a lifestyle intervention combining caloric restriction and exercise on cognitive function in a diverse sample of postmenopausal women with overweight or obesity and functional limitations. Methods: This study represents a secondary analysis of a previously conducted pilot trial, in which 34 participants were randomly assigned to a 24-week intervention: (i) caloric restriction plus exercise (CR + E; n = 17) or (ii) educational control (EC; n = 17). In the CR + E group, participants engaged in group-based weight management focused on caloric restriction and three weekly exercise sessions, including walking and lower-body resistance training. The EC group attended monthly health education lectures. Changes in cognitive scores were assessed using the Digit Symbol Substitution Test (DSST) and the Controlled Oral Word Association (COWA) test. Additionally, we explored the correlation between changes in cognitive scores and physical function in the CR + E group. Results: In the CR + E group, DSST scores significantly improved compared to the EC group (p < 0.05). There were no significant changes in COWA scores for either group compared to their baseline value or between groups. Furthermore, changes in DSST or COWA were not significantly correlated with changes in walking speed or physical function. Conclusions: The preliminary results of this study suggest that CR + E may improve complex attention in functionally limited postmenopausal women with overweight or obesity but does not appear to significantly affect verbal fluency. Full article

The sterol demethylation inhibitors (DMIs) are among the most widely used fungicides for controlling black Sigatoka (Mycosphaerella fijiensis) and yellow Sigatoka (Mycosphaerella musicola) in banana plantations in Brazil. Black Sigatoka is considered more important due to causing yield losses of up to 100% in commercial banana crops under predisposing conditions. In contrast, yellow Sigatoka is important due to its widespread occurrence in the country. This study aimed to determine the current sensitivity levels of Mf and Mm populations to DMI fungicides belonging to the chemical group of triazoles. Populations of both species were sampled from commercial banana plantations in Registro, Vale do Ribeira, São Paulo (SP), Ilha Solteira, Northwestern SP, and Janaúba, Northern Minas Gerais, and were further characterized phenotypically. Additionally, allelic variation in the CYP51 gene was analyzed in populations of these pathogens to identify and characterize major mutations and/or mechanisms potentially associated with resistance. Sensitivity to the triazoles propiconazole and tebuconazole was determined by calculating the 50% inhibitory concentration of mycelial growth (EC₅₀) based on dose–response curves ranging from 0 to 5 µg mL⁻¹. Variation in sensitivity to fungicides was evident with all nine Mf isolates showing moderate resistance levels to both propiconazole or tebuconazole, while 11 out of 42 Mm strains tested showed low to moderate levels of resistance to these triazoles. Mutations leading to CYP51 substitutions Y136F, Y461N/H, and Y463D in Mm and Y461D, G462D, and Y463D in Mf were associated with low or moderate levels of resistance to the triazoles. Interestingly, Y461H have not been reported before in Mm or Mf populations, and this alteration was found in combination with V106D and A446S. More complex CYP51 variants and CYP51 promoter inserts associated with upregulation of the target protein were not detected and can explain the absence of highly DMI-resistant strains in Brazil. Disease management programs that minimize reliance on fungicide sprays containing triazoles will be needed to slow down the further evolution and spread of novel CYP51 variants in Mf and Mm populations in Brazil. Full article

To mitigate the serious environmental impact caused by the persistent accumulation of plastics, replacing conventional plastics with paper-based alternatives has emerged as a promising trend. In response to the environmental and health concerns associated with petrochemical-based plastic meal boxes and fluorinated water- and oil-repellent agents, this study proposes a sustainable, fluorine-free coating technology based on chitosan to enhance the water and oil resistance of molded-paper pulp meal boxes. By adjusting the degree of deacetylation and the solution concentration of chitosan, coated meal boxes were fabricated via a spraying method. The results demonstrate that coatings prepared with highly deacetylated (>95%) and concentrated (4% w/v) chitosan significantly improve barrier properties, achieving a water contact angle of 114.9° ± 3°, the highest oil-resistance rating (12/12) according to TAPPI standards, and stable resistance to 95 °C hot oil for up to 30 min without leakage. In addition, the coated samples exhibit enhanced mechanical strength (21.26 MPa) and excellent biodegradability. This work provides a cost-efficient and eco-friendly disposable food packaging solution, facilitating the sustainable substitution of petrochemical-based plastics. Full article

Background: Several targeted drugs have been recently approved for the treatment of PIK3CA-mutated hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC). This study aimed at a comprehensive evaluation of the spectrum of PIK3CA alterations in Russian BC patients. Methods: The tumor material from 1872 patients with ER+/HER2− BC was tested by a combination of PCR-based methods. Results: Mutations were detected in 693/1872 (37%) cases, including 46 BC with two PIK3CA lesions. The three most common substitutions (E542K, E545K, and H1047R) were identified in 542/693 (78%) PIK3CA-mutated cases, while as many as 5.5–12% of identified mutations were not potentially detectable by common commercial kits. The study included patients of Slavic and non-Slavic ethnicities residing in regions with different climate conditions, however, these factors did not influence the distribution of PIK3CA mutations. The presence of PIK3CA variants was associated with older patient age at diagnosis (p = 0.0002), smaller tumor size (p = 0.005), lower grade (p = 0.005), Ki67 <20% (p = 0.0001) and progesterone receptor-positive status (p = 0.002) at the initial disease diagnosis, and fewer distant metastases at the time of the detection of BC spread (p = 0.0001). In a subgroup of 413 BC patients who received adjuvant tamoxifen or aromatase inhibitors, PIK3CA mutations were not associated with resistance to either type of treatment. Conclusions: The results of this study highlight the need to extend the PIK3CA testing beyond the hotspot regions of this gene. Although PIK3CA alterations contribute to the pathogenesis of HR+/HER2− BC and represent a target for several novel drugs, they are not intrinsically associated with unfavorable clinical characteristics of this subtype of cancer disease. Full article

Recently, increased global awareness of environmental sustainability and ethical consumerism has amplified the demand for sustainable alternatives to animal-derived leather. Traditional leather manufacturing faces significant ethical and ecological challenges, including greenhouse gas emissions, excessive water consumption, deforestation, and toxic chemical usage. Vegan leather has emerged as a promising solution, predominantly fabricated from petroleum-based synthetic materials such as polyurethane (PU) and polyvinyl chloride (PVC). However, these materials have sustainability limitations due to their non-biodegradability and associated environmental burdens. To overcome these issues, this review critically explores the feasibility of developing vegan leather using gel-based materials derived from natural and synthetic polymers. These materials offer precise structural controllability, excellent biodegradability, and the potential for significantly improved mechanical performance through hybridization and nanocomposite strategies. Despite their promising attributes, gel-based materials face significant limitations, including insufficient tensile strength, poor abrasion resistance, susceptibility to swelling, limited long-term stability, and challenges in scaling up for industrial production. This paper outlines the structural and physical properties required for viable leather substitutes, reviews opportunities provided by gel-based materials, addresses associated technical challenges, and proposes comprehensive strategies for enhancing mechanical properties and developing sustainable, eco-friendly production processes. Future research directions emphasize hybrid composite development, nanoparticle integration, circular manufacturing processes, and multi-disciplinary collaboration to establish gel-based vegan leather as a viable, sustainable, and market-competitive alternative to conventional animal leather. Full article

Background/Objectives: Achromobacter xylosoxidans and Achromobacter insuavis are emerging opportunistic pathogens. Several Resistance-Nodulation-cell Division (RND) efflux systems are involved in intrinsic or acquired antibiotic resistance (AxyABM, AxyXY-OprZ, and AxyEF-OprN). The aim of this study was to explore the resistance mechanisms in one-step mutants in which the efflux systems described to date are not involved: one mutant of A. insuavis AXX-A (AXX-A-Do1) and two mutants of A. xylosoxidans CIP102236 (CIP102236-El9 and CIP102236-Eo4) selected on fluoroquinolones. Methods: In vitro mutants were compared to parental isolates by WGS. RT–qPCR and gene inactivation were used to explore the role of the new efflux systems detected. Results: In the A. insuavis AXX-A mutant (AXX-A-Do1), WGS showed a substitution in the putative regulator of the new RND efflux system AinCDJ. The transporter gene ainD was 79-fold overexpressed in AXX-A-Do1, compared to its parental strain. The inactivation of ainD in AXX-A-Do1 led to a decrease in MICs of ciprofloxacin (8-fold), levofloxacin (8-fold), cefepime (≥8-fold), meropenem (4-fold), doripenem (4-fold), doxycycline (4-fold), minocycline (4-fold), tigecycline (4-fold) and chloramphenicol (≥8-fold). The MICs values obtained were similar to those of the parental strain AXX-A. The same approach allowed the detection of the new efflux system AxySUV in A. xylosoxidans CIP102236 mutants, in which substitutions in the putative AxySUV regulator were associated with the overexpression of the transporter gene axyU. axyU inactivation in the mutants led to a decrease in MICs of ciprofloxacin (8- to 16-fold), levofloxacin (4- to 8-fold), doripenem (4-fold), doxycycline (4-fold), minocycline (4-fold), and chloramphenicol (≥4-fold). Interestingly, axySUV is present in only about 50% of available A. xylosoxidans genomes, whereas ainCDJ is detected in all A. insuavis genomes. Conclusions: This study demonstrated that AinCDJ overproduction is involved in the acquired resistance of A. insuavis to cefepime, meropenem, doripenem, fluoroquinolones, minocycline, doxycycline, tigecycline, and chloramphenicol and that AxySUV overproduction is involved in the acquired resistance of A. xylosoxidans to meropenem, fluoroquinolones, minocycline, doxycycline, and chloramphenicol. Full article

Electrical transport in 2D materials exhibits unique behaviors due to reduced dimensionality, broken symmetries, and quantum confinement. It serves as both a sensitive probe for the emergence of coherent electronic phases and a tool to actively manipulate many-body correlated states. Exploring their interplay and interdependence is crucial but remains underexplored. This review integratively cross-examines the atomic and electronic structures and transport properties of van der Waals-layered crystals ZrTe₃, 2H-TaS₂, and Cr₂Si₂Te₆, providing a comprehensive understanding and uncovering new discoveries and insights. A common observation from these crystals is that modifying the atomic and electronic interface structures of 2D van der Waals interfaces using heteroatoms significantly influences the emergence and stability of coherent phases, as well as phase-sensitive transport responses. In ZrTe₃, substitution and intercalation with Se, Hf, Cu, or Ni at the 2D vdW interface alter phonon–electron coupling, valence states, and the quasi-1D interface Fermi band, affecting the onset of CDW and SC, manifested as resistance upturns and zero-resistance states. We conclude here that these phenomena originate from dopant-induced variations in the lattice spacing of the quasi-1D Te chains of the 2D vdW interface, and propose an unconventional superconducting mechanism driven by valence fluctuations at the van Hove singularity, arising from quasi-1D lattice vibrations. Short-range in-plane electronic heterostructures at the vdW interface of Cr₂Si₂Te₆ result in a narrowed band gap. The sharp increase in in-plane resistance is found to be linked to the emergence and development of out-of-plane ferromagnetism. The insertion of 2D magnetic layers such as Mn, Fe, and Co into the vdW gap of 2H-TaS₂ induces anisotropic magnetism and associated transport responses to magnetic transitions. Overall, 2D vdW interface modification offers control over collective electronic behavior, transport properties, and their interplays, advancing fundamental science and nanoelectronic devices. Full article

Campylobacter spp. is one of the most prevalent causes of zoonotic foodborne infections associated with diarrhea in humans. The growing threat of antibiotic resistance calls for innovative approaches. The antimicrobial lipopeptide brevibacillin produced by Brevibacillus laterosporus and its synthetic analog brevibacillin Thr1 showed promising activity against Salmonella and E. coli. The latter is a 1602.13 Da positively charged (+3) synthetic peptide of 13 residues that showed reduced cytotoxicity (IC₅₀ of 32.2 µg/mL against Caco-2 cells) and hemolytic activity (1.2% hemolysis at 128 µg/mL) compared to the native peptide. It contains an N-terminal L-isoleucic fatty acid chain and four non-proteinogenic amino acids and ends with valinol at its C-terminus. One key structural modification is the substitution of α,β-dehydrobutyric acid with threonine. We investigated the antimicrobial potential of the synthetic brevibacillin Thr1 analog against a collection of 44 clinical Campylobacter spp. that were obtained from two reference laboratories. Susceptibility testing revealed marked resistance to ciprofloxacin, tetracycline, and ampicillin among the strains, with more than half expressing a multidrug-resistant phenotype. The genomes of the 44 strains were sequenced to study the genes responsible for their antimicrobial resistance. Tetracycline resistance was associated with tet(O), ciprofloxacin resistance with mutations in gyrA and regulatory sequences modulating the expression of an efflux system, and aminoglycoside resistance with genes of the aph family. The brevibacillin Thr1 analog was produced by chemical synthesis, and evaluation of its activity against a subset of clinical strains by microdilution revealed minimum inhibitory concentration and minimum bactericidal concentration ranging from 8 µg/mL to 64 µg/mL. The peptide was active against multidrug-resistant isolates with a bactericidal effect. Of note, despite numerous attempts, it proved impossible to select Campylobacter spp. for resistance to the brevibacillin Thr1 analog. These results underline the potential of lipopeptides, notably brevibacillin, as antimicrobial alternatives against antibiotic-resistant Campylobacter bacterial infections. Full article

The development of new, more effective, and selective anticancer agents is one of the most important tasks of modern medicinal chemistry. Recently, we have found that non-classical Pd(II) pincer complexes derived from thiophosphoryl-appended picolinamides exhibit promising cytotoxic properties. In this work, the potential of this class of metal-based derivatives was studied on an extended family of Pd(II) complexes with a deprotonated amide core featuring thiophosphoryl pendant arms, readily obtained by the direct cyclopalladation of new functionalized amide ligands upon interaction with PdCl₂(NCPh)₂ under mild conditions. The ligands, in turn, were obtained by conventional amide coupling methods using (aminobenzyl)- and (aminomethyl)diphenylphosphine sulfides as the key precursors and different N- and S-donor-substituted carboxylic acids. The effect of an acid component and carbon chirality in the ligand framework on the bioactivity of the resulting Pd(II) pincer complexes was elucidated by evaluating their cytotoxicity against different solid and blood cancer cell lines, apoptosis induction ability, and P-glycoprotein (P-gp) affinity, which revealed the high anticancer potential of some of them, and in particular, the potential to overcome drug resistance associated with P-gp overexpression. The representative palladocycle was also shown to possess moderate antibacterial activity. Full article

The indoor microbiome is a dynamic ecosystem including pathogens that can impact human health. In this regard, the school environment represents the main living space of humans for many years, and an unhealthy environment can significantly condition students’ health. School rooms can suffer from insufficient ventilation and the use of building materials that may favor pathogen contamination, mostly sanitized by conventional chemical-based methods, which can impact pollution, have temporary effects, and induce the selection of antimicrobial resistance (AMR) in persistent microbes. In the search for sustainable and effective methods to improve the healthiness of the classroom environment, a pre–post case–control study was performed in an Italian high school. Over a year, different interventions were sequentially placed and evaluated for their impact on bioburden and air quality, including the introduction of plants, a mechanical ventilation system, and probiotic-based sanitation (PBS) in substitution for chemical sanitation. Through continuous microbial monitoring of the enrolled school rooms, via culture-dependent and -independent methods, a remarkable bioburden level was detected at baseline (around 12,000 and 20,000 CFU/m², before and after classes, respectively), composed mostly of Staphylococcus spp. and fungi. Some decrease in fungal contamination was observed following the introduction of plants. Still, the most significant decrease in pathogens and associated AMR was detected following the introduction of ventilation and PBS, which decreased pathogen level by >80% (p < 0.001) and AMR by up to 3 Log₁₀ (p < 0.001) compared to controls. Collected data support the use of combined strategies to improve indoor microbial quality and confirm that PBS can effectively control bioburden and AMR spread not only in sanitary environments. Full article

Background/Objectives: Oxazolidinones are novel antimicrobial agents used to combat bacterial infections, particularly multidrug-resistant strains. However, the synthesis of oxazolidinone derivatives, such as linezolid, often involves the use of 3,4-difluoronitrobenzene (DFNB) as an initiator. Despite its effectiveness, residual DFNB in drug products raises significant health concerns due to its structural similarity to toxic and carcinogenic nitrobenzenes. This contamination is particularly concerning in pharmaceutical formulations, where it poses potential patient safety hazards. Therefore, strict concentration limits for this impurity are necessary. Methods: To ensure tight control of DFNB concentrations, this study established an 8.3 µg/g target limit. An advanced high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to overcome current limitations in detecting trace DFNB. Under negative atmospheric pressure chemical ionization (APCI) conditions, DFNB exhibited characteristic ion formations, including [M]^•− through electron capture and [M − F + O]⁻ via substitution reactions. The quantitative method utilizes MS/MS ion transitions of the substitution product while optimizing chromatographic and spectrometric parameters to enhance both sensitivity and specificity. Conclusions: Validation tests confirm the efficiency, precision, and accuracy of this method, with a low limit of quantification (LOQ) of 5 ng/mL (0.83 µg/g). This technique enables accurate detection and quantification of DFNB in linezolid active pharmaceutical ingredient (API) and various formulations, providing a reliable tool for quality control. This method ensures the safe use of linezolid by effectively monitoring and minimizing the risks associated with DFNB contamination. Full article

The ever-growing environmental and sustainability awareness as well as the associated increased independence from petroleum has led to bio-based materials increasingly replacing synthetic, non-renewable materials in various applications, including food packaging, coatings, adhesives, and energy storage devices. Although bio-based materials offer advantages such as reduced toxicity and harmfulness for humans and the environment, as well as contributing to the conservation of important resources, these aspects are usually not sufficient for commercialization. Integrating bio-based materials into existing technologies is challenging due to inherent disadvantages, such as difficult processability and low moisture resistance, making it difficult to readily substitute them for synthetic materials. Consequently, surface modifications are often necessary to make bio-based materials suitable for the intended applications. This review highlights the critical role of processing methods in the successful substitution of synthetic materials with bio-based alternatives. While previous studies have primarily concentrated on material combinations and formulations of bio-based applications, often considering processing methods as secondary, this review explores the influence and importance of dispersion quality. It examines how varying dispersing methods and process parameters can impact the performance of bio-based materials, alongside addressing the specific requirements for both the materials and the dispersing processes. Furthermore, it focuses on bio-based dispersions based on lignin and polysaccharides, particularly in applications such as bio-based adhesives and binders for battery technologies. By addressing these aspects, this review aims to reveal existing research gaps and provide insights into optimizing the processing of bio-based materials for diverse applications. Full article

Tryptophan hydroxylase 2 (TPH2) hydroxylates L-tryptophan to L-5-hydroxy tryptophan—the key step of 5-HT synthesis in the mammalian brain. Some mutations in the human hTPH2 gene are associated with psychopathologies and resistance to antidepressant therapy. The C1473G polymorphism in the mouse Tph2 gene decreases the TPH2 activity in the mouse brain. In the present paper, B6-1473C and B6-1473G congenic mice that were different only in the C > G substitution were used. The molecular mechanism of decrease in the mutant enzyme activity and some physiological and behavioral traits affected by this mutation were revealed for the first time. Analysis of thermal denaturation curves in vitro revealed that the C > G substitution reduces the free energy of denaturation, stability and lifetime of mutant TPH2. Later, we evaluated the effect of the 1473G allele on the hierarchical state, competition for a sexual partner in adult mice, mouse embryos, hind legs dystonia and the response to LPS treatment in young mice. No effect of this mutation on the hierarchical state and competition for a female was observed in adult males. The C > G substitution does not affect survival, body mass or the TPH activity in the brain of 19-day-old mouse embryos. At the same time, we found that the 1473G allele causes hind legs dystonia in juvenile (3 weeks old) mice, which can affect their escape capability in threatening situations. Moreover, a significant increase in the vulnerability to LPS in juvenile B6-1473G males was shown: a single ip LPS administration killed about 40% of young mutant mice, but not wild-type ones. The body mass of mutant males was lower compared to wild-type ones, which also can indirectly decrease their concurrent and reproductive success. Full article