Designing mRNA- and Peptide-Based Vaccine Construct against Emerging Multidrug-Resistant Citrobacter freundii: A Computational-Based Subtractive Proteomics Approach.

Background and Objectives: Citrobacter freundii (C. freundii) is an emerging and opportunistic Gram-negative bacteria of the human gastrointestinal tract associated with nosocomial and severe respiratory tract infections. It has also been associated with pneumonia, bloodstream, and urinary tract infections. Intrinsic and adaptive virulence characteristics of C. freundii have become a significant source of diarrheal infections and food poisoning among immune-compromised patients and newborns. Impulsive usage of antibiotics and these adaptive virulence characteristics has modulated the C. freundii into multidrug-resistant (MDR) bacteria. Conventional approaches are futile against MDR C. freundii. Materials and Methods: The current study exploits the modern computational-based vaccine design approach to treat infections related to MDR C. freundii. A whole proteome of C. freundii (strain: CWH001) was retrieved to screen pathogenic and nonhomologous proteins. Six proteins were shortlisted for the selection of putative epitopes for vaccine construct. Highly antigenic, nonallergen, and nontoxic eleven B-cell, HTL, and TCL epitopes were selected for mRNA- and peptide-based multi-epitope vaccine construct. Secondary and tertiary structures of the multi-epitope vaccine (MEVC) were designed, refined, and validated. Results: Evaluation of population coverage of MHC-I and MHC-II alleles were 72% and 90%, respectively. Docking MEVC with TLR-3 receptor with the binding affinity of 21.46 (kcal/mol) occurred through the mmGBSA process. Further validations include codon optimization with an enhanced CAI value of 0.95 and GC content of about 51%. Immune stimulation and molecular dynamic simulation ensure the antibody production upon antigen interaction with the host and stability of the MEVC construct, respectively. Conclusions: These interpretations propose a new strategy to combat MDR C. freundii. Further, in vivo and in vitro trials of this vaccine will be valuable in combating MDR pathogens.

Successful Co-administration of Dupilumab and Anti-tuberculosis Drugs in a Severely Uncontrolled Asthma Patient With Pulmonary Tuberculosis.

The co-occurrence of active tuberculosis (TB) in patients with moderate to severe asthma presents unique therapeutic challenges, particularly with the advent of biologics like dupilumab, which targets the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways in asthma treatment. Despite the general safety of biologics, concerns about immunosuppression and susceptibility to infections like TB persist. This case report discusses a male with severe, uncontrolled type 2 allergic asthma, who experienced multiple exacerbations despite maximal bronchodilator therapy and then concomitantly developed pulmonary TB. This case demonstrates a potential clinical scenario for co-administering dupilumab with anti-TB treatment, suggesting a beneficial approach for similar clinical scenarios and contributing to the literature on this topic.

Biomass fly ash as nanofiller to improve the dielectric properties of low-density polyethylene for possible high-voltage applications.

Flexible capacitive energy storage applications require polymer nanocomposites with high dielectric properties, which can be accomplished by addition of inorganic nanofillers to the polymer matrix. Low-density polyethylene (LDPE), known for its good dielectric characteristics and wide use in electrical insulation have been investigated for the desired applications. However, the improvement of its breakdown strength still continues with the use of various nanomaterials employed as nanofillers. In this study, a waste-derived material known as biomass fly ash (BFA) as a nanofiller to improve the dielectric properties of LDPE has been explored. BFA exhibits versatility in its composition with various metal oxides, making it an attractive choice as a nanofiller. The BFA-LDPE sheets were prepared using a conventional solvent mixing and subsequent hot-pressing process, incorporating BFA loadings ranging from 1 % to 4 wt%. The effects of different BFA loadings were carefully examined, and the synthesized nanocomposites were extensively characterized using various characterization methods, such as XRD, SEM, FTIR, TGA and dielectric constant measurements, to investigate the crystallographic properties, morphology, chemical composition, and thermal stability. Among all the nanocomposites, 4 wt%BFA-LDPE exhibited the highest dielectric constant, with a value of 11.58, compared to simple LDPE that had a dielectric constant of 8.33. This improvement is ascribed to the synergistic effects of different inorganic metal oxides (SiO2, MgO, and Fe2O3) present in BFA. The results showed a significant enhancement in dielectric properties, indicating that the waste-derived BFA can be purposefully applied as an effective nanofiller in the LDPE-based composites with even less than 4% loading for electrical insulating applications in future studies.

The spectrum of genetic mutations in breast cancer.

Breast cancer is the most common malignancy in women around the world. About one in 12 women in the West develop breast cancer at some point in life. It is estimated that 5%-10% of all breast cancer cases in women are linked to hereditary susceptibility due to mutations in autosomal dominant genes. The two key players associated with high breast cancer risk are mutations in BRCA 1 and BRCA 2. Another highly important mutation can occur in TP53 resulting in a triple negative breast cancer. However, the great majority of breast cancer cases are not related to a mutated gene of high penetrance, but to genes of low penetrance such as CHEK2, CDH1, NBS1, RAD50, BRIP1 and PALB2, which are frequently mutated in the general population. In this review, we discuss the entire spectrum of mutations which are associated with breast cancer.