The objective of this study is to determine the design space (DS) for a dissolution-enhanced gemifloxacin immediate-release (IR) tablet incorporating hydroxypropyl-β-cyclodextrin (HPCD) for improved solubility, utilizing a quality by design (QbD) approach. Based on the preliminary studies, hardness, friability, disintegration time, assay, content uniformity, and dissolution rate were identified as the critical quality attributes (CQAs) for optimization. Through the initial risk assessment, crospovidone, main compression force, and the amount of granulating fluid were identified as factors influencing the CQAs, and a 2[3] + 3 full factorial design of experiments (DoE) was conducted for optimization. According to the analysis of variance (ANOVA), both main compression force (p = 0.004) and the amount of granulating fluid (p = 0.001) significantly affected hardness. While the amount of granulating fluid was established as a primary factor influencing disintegration time (p = 0.001) and dissolution rate (p = 0.006). The other factors did not show a statistically significant impact on the remaining CQAs. The optimized ranges obtained from this study were as follows: crospovidone, 5.72-7.99%; main compression force, 1707.5-2372.3 kgf; and amount of granulating fluid, 5.36-6.12 mL. A 2[3] + 3 full-factorial design of experiments (DoE) was applied to determine the relationship between independent and dependent variables, and a high-quality IR tablet meeting all predefined CQA criteria [hardness (18.0-22.0 kp), friability (≤0.5%), disintegration time (16.0-20.0 min), assay (95.0-105.0%), content uniformity (AV ≤ 5), and dissolution similarity (f2 ≥ 50)] was developed through the systematic optimization of formulation and manufacturing processes.

Early deception poses a representational puzzle: young children can strategically deny and conceal transgressions before they reliably succeed on standard measures of false-belief understanding. Standard interpretations often force a choice between two unsatisfying extremes: either early deceptive behavior is reduced to a routine punishment-avoidance response, or it is taken to imply a surprisingly rich capacity for belief representation. This paper develops an intermediate alternative. Early deception is argued to be better explained by an access-based epistemic policy that tracks another agent's epistemic standing, specifically whether that agent is in a position to know, on the basis of perceptual access, evidential availability, and blocking conditions. This proposal is developed as a policy framework in which actions such as denial, concealment, and withholding are selected under uncertainty as functions of graded epistemic standing. The developmental literature is treated not as the paper's main payload, but as a constraint on representational format. The resulting pattern is asymmetric: young children show flexible sensitivity to witness access, audience knowledge, and opportunities for concealment, yet remain brittle under follow-up questioning, semantic leakage, and evidence-coordinated cover-story demands. This pattern is best understood as evidence for a factive, access-based form of epistemic mindreading that precedes robust belief-based deception.

This study was conducted to determine the potential effect of other antimicrobial agents on the in vitro activity of gepotidacin against six WHO N. gonorrhoeae and QC strain ATCC 49226 by checkerboard assays using Graver-Wade broth. Synergy and antagonism were evaluated using fractional inhibitory concentration (FIC) and FIC index (FICI) results for gepotidacin and comparator agents (azithromycin, cefixime, ceftriaxone, gemifloxacin, sitafloxacin, gentamicin, spectinomycin, doxycycline, and lefamulin). The evaluation of FICI showed no antagonistic or synergistic interactions, while the evaluation of individual FIC values revealed strain- and agent-specific synergistic or additive effects.

Tuberculosis (TB) remains a global health threat, with multidrug-resistant TB (MDR-TB) presenting major therapeutic challenges. Fluoroquinolones (FQs) are key second-line drugs. Resistance is typically linked to mutations within quinolone resistance-determining regions (QRDRs), though non-canonical mechanisms are increasingly recognized. To evaluate phenotypic susceptibility to gemifloxacin in clinical Mycobacterium tuberculosis isolates and determine the association with mutations in gyrA and gyrB QRDRs. Sixty clinical isolates (40 drug-susceptible [DS], 20 MDR) were tested using the resazurin microtiter assay (REMA). Minimum inhibitory concentrations (MICs) ranged from 0.25 to 128 µg/mL. Resistance was defined using an epidemiological cutoff value (ECOFF) of ≥8 µg/mL. Sanger sequencing of QRDR hotspots in gyrA (codons 90, 91, 94) and gyrB (codons 500-540) was performed on all six resistant isolates and two susceptible controls. MDR isolates exhibited significantly higher median MICs compared to DS isolates (4 µg/mL vs 2 µg/mL, P = 0.04). Six isolates (10%) were phenotypically resistant, including two DS and four MDR strains. Given our modest sample size (n = 60), no mutations were detected within the sequenced QRDR segments of gyrA and gyrB in any resistant isolate or control. In this hypothesis-generating study, gemifloxacin resistance was observed in M. tuberculosis without mutations in the sequenced QRDR regions of gyrA/gyrB, implying alternative mechanisms, such as efflux pump activity or altered permeability. While limited by sample size, these preliminary findings challenge the reliance on molecular diagnostics targeting only QRDRs and underscore the importance of phenotypic testing for accurate detection of resistance. Larger multicenter studies are warranted to validate these observations and elucidate the underlying mechanisms.IMPORTANCEThis study provides the first evidence that Mycobacterium tuberculosis can develop phenotypic resistance to gemifloxacin-despite having no mutations in the canonical gyrA/gyrB quinolone resistance-determining regions (QRDRs). Among 60 clinical isolates, 10% of gemifloxacin-resistant strains were QRDR-negative. Although gemifloxacin is no longer used clinically due to toxicity, its unique structure reveals hidden, non-target-based resistance mechanisms (e.g., efflux, permeability changes) that likely also compromise current fluoroquinolones like levofloxacin and moxifloxacin. This exposes a critical blind spot: current molecular diagnostics (e.g., Xpert MTB/XDR, GenoType) may falsely label resistant strains as susceptible, risking treatment failure. We argue that phenotypic drug susceptibility testing (DST) must be mandatory-not optional-in multidrug-resistant tuberculosis (MDR-TB) programs to safeguard against this silent, undetected resistance.

The capacity to represent the mental states of other individuals, known as 'mindreading' or 'theory of mind', is key to successful social prediction. We suggest that cognitive systems for mindreading are resource-rational: they are optimized for generating good predictions about the behaviour of other individuals, while not exceeding the computational capacity of the mindreader. We explore this hypothesis in a simple formal model where we derive cognitive strategies that excel at social prediction while minimizing cognitive effort. We find that it is often optimal for resource-limited mindreaders to keep track of the facts that another agent also knows, instead of explicitly representing the content of the agent's beliefs. When evaluated in mindreading tasks, simulated agents that use this 'factive' strategy tend to make mistakes in the same cases as non-human primates and young human children. Even agents that use more sophisticated strategies avoid representing beliefs unless necessary. Our results elucidate the computational principles underlying efficient social prediction and explain many of the successes and failures of human and non-human mindreading from first principles.

Fluoroquinolones (FQs) are among the most frequently prescribed antibiotic classes worldwide. Despite their therapeutic versatility in treating bacterial infections, regulatory authorities recognized risks of persistent and potentially irreversible adverse effects, particularly peripheral neuropathy (PN). However, a comprehensive pharmacovigilance assessment of PN-related adverse events (AEs) across all six FDA-approved FQs remains limited. We therefore analyzed adverse event reports (AERs) associated with these six agents from the FDA Adverse Event Reporting System (FAERS) Public Dashboard spanning 2007-2024 Q3, following READUS-PV guidelines. Disproportionality analysis was conducted to identify potential safety signals for PN-related AEs reported with FQ use following deduplication and exclusion of cases involving non-FQ concomitant medications. Positive disproportionality signals were observed for the commonly prescribed FQs (ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin), with seven distinct PN manifestations generating signals. Notably, we detected PN-related signals for gemifloxacin, a relatively new FQ with limited prior evaluation of neurotoxicity. Univariate logistic regression revealed that women and adults aged 18-64 years were more frequently represented in FQ-associated PN-related AERs, whereas men and patients aged ≥ 65 years were disproportionately represented among cases with fatal outcomes. Combination therapy with multiple FQs generated disproportionality signals exceeding those with FQ monotherapy. These findings underscore the need for increased vigilance when prescribing FQs, particularly for mild infections where risks may outweigh benefits. Strengthened clinical monitoring for early signs of PN is advisable when FQ treatment becomes unavoidable. Further controlled epidemiological studies are needed to validate these signals and define at-risk groups, alongside mechanistic research aimed at supporting the development of neuroprotective strategies.

PURPOSE: Combination treatments can shorten treatment time and reduce drug side effects. The aim of this study was to assess the efficacy of combined treatment using bedaquiline (BDQ) against clinical isolates of multidrug-resistant (MDR) Mycobacterium tuberculosis (M. tuberculosis). METHODS: This cross-sectional study was performed on 15 drug-resistant isolates of M. tuberculosis. After determining the Minimum inhibitory concentration (MIC) of antibiotics, the fractional inhibitor concentration index (FICI) was evaluated using a checkerboard resazurin microtitration assay (REMA) to evaluate their interaction profiles against the M. tuberculosis isolates. The macrophage model was used to study the activity of synergistic compounds and the expression level of macrophage genes were evaluated by real-time PCR. RESULTS: All isolates had MIC ≥ 0.25 µg/mL for BDQ. Of the 15 isolates, only 2 observed a synergistic effect between BDQ and other antibiotics. The expression of macrophage genes (FABP5, HERG, RPL24, and SCARB1) infected with these two isolates, was significantly increased by the combination of BDQ+ gemifloxacin (GEM), BDQ + Rifampicin (RIF), BDQ + moxifloxacin (MFX), and BDQ + isoniazid (INH) (p < 0.01). CONCLUSION: Despite resistance to BDQ, the combination treatments showed a positive effect in the macrophage cell line model. Therefore, it can be concluded that the combination treatment with BDQ may enhanced the innate immune response of macrophages against M. tuberculosis infection and also reduce the MIC of BDQ and other antibiotics in combination with it. This suggests a potential for more effective treatment for drug-resistant isolates.

Background/Objectives: Discriminating bacterial from mammalian membranes remains a central challenge in antibiotic design. Bacterial membranes are enriched in phosphatidylethanolamine (PE), a lipid normally absent from the outer leaflet of mammalian cells, providing a signature for selective molecular engagement. We report a compact covalent ligand, 6-dimethylamino-4-ketohexanoic acid (DMAX), which targets PE via Schiff base formation, leveraging its tertiary amine to facilitate the reaction and strengthen ionic binding with the phosphate group. Methods: The reactivity of DMAX and PE was evaluated by computational simulations, and their interaction was examined by spectroscopic analyses (NMR and FT-IR) and an artificial membrane assay. The targeting ability of DMAX for live bacteria was determined by microscopy study, and its applicability to therapeutic system was tested in vitro under washed conditions that mimic rapid in vivo clearance. Results: Spectrometric analyses revealed the selective covalent interaction of DMAX and PE, consistent with the simulated results. Fluorescently labeled DMAX selectively binds PE-enriched model membranes and efficiently recognizes Gram-negative bacteria while sparing mammalian cells. Conjugation of DMAX to Gemifloxacin (Gem) significantly enhanced antibiotic efficacy by 10-fold compared with free Gem, even after rapid drug clearance, while maintaining safety in mammalian cells. Conclusions: These results identify DMAX as an efficient and versatile PE-targeting platform, enabling selective membrane anchoring to advance precision antibiotic strategies.

Fluoroquinolones are a class of widely used antibiotics, most of which contain chiral centers. Significant differences exist between their enantiomers in terms of antimicrobial activity, pharmacokinetics, and toxicity. In this study, glucosamine chiral-functionalized carbon quantum dots (GA-CQDs) were successfully synthesized and employed as a pseudostationary phase. By optimizing the chromatographic conditions, an efficient and novel chiral separation platform based on capillary electrophoresis (CE) was established for the enantioseparation of six fluoroquinolones. Compared to the CE system using free glucosamine solely as the chiral selector, the CE system employing GA-CQDs as a pseudostationary phase demonstrated a substantial improvement in chiral resolution (Rs) for all six model analytes (Ofloxacin: 1.56 → 9.21; Pazufloxacin: 0 → 8.53; Prulifloxacin: 1.38 → 7.58; Lomefloxacin: 1.01 → 2.84; Gemifloxacin: 0 → 1.25; Balofloxacin: 0 → 0.88). The incorporation of the pseudostationary phase significantly enhanced the chiral separation capability. This proposed strategy is characterized by its operational simplicity and low cost, thereby offering a valuable conceptual framework and a highly promising approach for developing chiral separation methods for fluoroquinolone antibiotics. This study represents the first report on employing GA-CQDs as a chiral selective medium to construct a capillary electrophoresis system, which achieved satisfactory enantioselectivity. Furthermore, the chiral recognition mechanism of glucosamine was preliminarily investigated through molecular modeling simulations, with the binding energy providing insights into the separation process.

Factive islands have been argued to be a late acquired phenomenon (de Villiers et al. (1998). Acquisition of the quantificational properties of mental pedicates. In A. Greenhill, M. Hughes, H. Littlefield, & H. Walsh (Eds.), Proceedings of the 22nd Boston University conference on language development. Somerville, MA: Cascadilla Press), but existing experimental studies have focused on a very limited number of factive verbs and report variation between verbs. Seventy monolingual Romanian-speaking children (split into two age groups: 5-year-old and 7-year-old children) and 15 adults took part in a comprehension task, which tested the (un)availability of adjunct extraction from the clausal complements of both cognitive and emotive factive verbs. The results show that only at age 7 do children begin to observe the restrictions imposed by factive islands, regardless of the sub-type of factive verb, even though they do not reach full mastery of the phenomenon at this age.

Herein, to address the challenges associated with microbial resistance against antibiotics, three new gemifloxacin derivatives (G-D08, G-D09 and G-D10), have been synthesized using conventional esterification (Fischer) and amide approach (C-3 and C-7 modified) in efficient yields. UV-Vis, FT-IR, [1]HNMR, and Mass spectroscopy for characterization while DFT studies for computational conformational stability. In-silico pharmacokinetics (Swiss ADME, Bio transformers) and toxicological properties (T.E.S.T software) evaluated that all derivatives followed Lipinski's criterion and exhibits no vital organ toxicity. Microbiological evaluation in reciprocation towards designated strains of Gram +ve and Gram -ve bacteria, and fungi demonstrated potent actuation towards K. pneumonia, Candida albicans and Citrobacter freundii in comparison to gemifloxacin, surpassing antibacterial and antifungal responsiveness, reinforced by B3LYP/6-311 G level of theory. Energy gaps (HOMO-LUMO) of derivative G-D09 and G-D10 is 1.72 eV determinant as cognizant. Molecular docking approach was also applied through MOE software against K. pneumonia (PDB ID: 6k63), C. freundii (PDB ID: 3JWB) and C. albicans (PDB ID: 1AI9) ranging between -6.05 and -7.79 kcal/ mol, authenticating their higher antibacterial response towards Klebsiella pneumoniae among all compounds and G-D10 as potent antifungal agent.

Ulcerative colitis is a Ulcerative colitis is a chronic inflammatory condition characterized by mucosal damage, oxidative stress, and elevated inflammatory mediators, necessitating innovative strategies. While sulfasalazine remains a standard treatment, alternative agents with dual antibacterial and anti-inflammatory effects are of growing interest. The goal of this study is to determine the ameliorative impact of gemifloxacin in comparison to sulfasalazine on inflammatory, oxidative, and histopathological alterations in a rat model of experimentally evoked ulcerative colitis. 40 Albino-Wistar rats were randomly divided into four groups of ten animals. All groups except Group I obtained a single intra-rectal dose of 4% acetic acid (vol/vol). Alternatively, Group I (Sham group) comprised healthy untreated rats who weren't getting any sort of therapy. Group II (control group) had undergone acetic acid-evoked colitis for one week and provided no medications. The rats in groups III (sulfasalazine) and IV (gemifloxacin) were administered 100 mg/kg of sulfasalazine and 50 mg/kg of gemifloxacin orally on a weekly basis, respectively. The histopathological scores of the colonic tissue, together with the following variables. Treatment with both gemifloxacin and sulfasalazine drastically lowered oxidative biomarkers, specifically malondialdehyde (MDA) and myeloperoxidase (MPO), compared to the colitis control group (p < 0.05). Moreover, both drugs significantly mitigated levels inflammatory biomarkers such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and nuclear factor kappa B (NF-κB) while attenuating levels of adhesive molecules like intercellular adhesive molecule (ICAM-1) and E-selectin compared to the colitis control group (p < 0.05). Additionally, they markedly improved the histopathological scores in acetic acid-aggravated-colonic histopathological scores. Gemifloxacin demonstrated remarkable anti-inflammatory, antioxidant, and tissue-protective impacts in a rat prototype of ulcerative colitis with therapeutic outcomes comparable to those of sulfasalazine. These findings support its promise as an adjuvant medication in controlling and managing inflammatory bowel diseases.

The practical application of conventional photocatalytic technologies in aquatic environmental remediation is significantly limited by rapid charge recombination and insufficient redox capacity. Theoretical calculations and experimental characterization confirmed that the synergistic co-doping of boron (B) and bismuth (Bi) induced tailored modifications to the band structures and Fermi level potential of g-C3N4 (CN) and ZnIn2S4 (ZIS), respectively, successfully transforming the type-II CN/ZIS heterojunction into an S-scheme B-doped CN/Bi-doped ZIS (BCN/BZIS) heterojunction. The subsequent integration of Cd0.5Zn0.5S (CZS) into the BCN/BZIS heterojunction introduced additional type-II and S-scheme photogenerated carrier transfer pathways, thereby establishing a hybrid BCN/BZIS/CZS heterojunction. This configuration exhibited exceptional reduction capacity and optimized photogenerated carrier separation and migration efficiency, leading to excellent degradation performance for gatifloxacin ((26.89 ± 1.94) × 10-2 min-1), sparfloxacin ((10.48 ± 2.03) × 10-2 min-1), moxifloxacin ((8.43 ± 1.02) × 10-2 min-1), and gemifloxacin ((4.13 ± 0.13) × 10-2 min-1). The degradation disparities among these quinolone antibiotics were systematically elucidated through analyses of steric hindrance, frontier molecular orbital energies, Mulliken charge distribution, reaction sites, and active species contribution rates. This study offers guidance for the systematic development of heterojunction photocatalysts to address fluoroquinolone pharmaceutical pollutants in aquatic ecosystems.

Understanding relative certainty and factivity of cognitive verbs (e.g., 'think', 'know') presents a significant challenge for both typically developing (TD) and autistic children. The first aim of the current study was to examine the understanding of these two aspects of cognitive verbs among autistic children compared to their TD peers. The second aim was to explore cognitive and linguistic capacities related to the development of cognitive verb understanding. 59 autistic and 62 TD children, ages 3 to 10 years, participated in a cross-sectional design that tested the comprehension of cognitive verbs in two tasks: understanding relative certainty and understanding factivity. In addition, children were tested in three tasks that evaluated Theory of Mind (TOM), vocabulary, and syntax. Autistic children had more difficulties than their TD peers in understanding the meaning of relative certainty and factivity of cognitive verbs. This difference was shown in both preschool and school-age children. Moreover, using logistic regression models, we found that age emerged as the sole predictor for comprehending cognitive verbs in TD children. For autistic children, TOM was the exclusive predictor for explaining factivity scores, and no predictor was identified for explaining relative certainty scores. The current research reveals a distinct linguistic difference in the comprehension of cognitive verbs between autistic and TD children. The results emphasize the link between understanding cognitive verbs and TOM abilities in autistic children. These results highlight the importance of focusing on the comprehension of cognitive verbs when assessing the language of autistic children.

Antibody-drug conjugates (ADCs) have drawn a lot of attention in the field of cancer therapy due to their improved efficacy and reduced side effects compared to traditional therapeutic antibodies or chemotherapeutics. However, cancer patients still develop resistance against ADCs and there is an urgent need for the development of strategies to reinforce ADC efficacy. Radiolabeling of an antibody with therapeutic radioisotopes (e.g., 177Lu or 225Ac) can be considered an option. Herein, we synthesized radiolabeled ADCs and evaluated their potential therapeutic efficacies in vitro and in vivo for cancer therapy. New trastuzumab-based ADCs utilizing fendiline or gemifloxacin as drug moieties were developed, and they were decorated with therapeutic radionuclide 177Lu or 225Ac. Anticancer effects of radiolabeled ADCs were evaluated using human epidermal growth factor receptor 2 (HER2) expressing cancer cells and compared to that of cold ADCs. Radiolabeled versions of newly synthesized ADCs showed significantly improved anticancer efficacy compared to unlabeled ADCs, especially when they were armed with 225Ac, demonstrating the great potential of radiolabeled ADCs in cancer therapy. This study offers an effective strategy for improving the therapeutic efficacy of ADCs by fortifying them with radionuclides.