The biosynthesis of the lincosamide antibiotics lincomycin A and celesticetin involves the pyridoxal-5'-phosphate (PLP)-dependent enzymes LmbF and CcbF, which are responsible for bifurcation of the biosynthetic pathways. Despite recognizing the same S-glycosyl-L-cysteine structure of the substrates, LmbF catalyses thiol formation through β-elimination, whereas CcbF produces S-acetaldehyde through decarboxylation-coupled oxidative deamination. The structural basis for the diversification mechanism remains largely unexplored. Here we conduct structure-function analyses of LmbF and CcbF. X-ray crystal structures, docking and molecular dynamics simulations reveal that active-site aromatic residues play important roles in controlling the substrate binding mode and the reaction outcome. Furthermore, the reaction selectivity and oxygen-utilization of LmbF and CcbF were rationally engineered through structure- and calculation-based mutagenesis. Thus, the catalytic function of CcbF was switched to that of LmbF, and, remarkably, both LmbF and CcbF variants gained the oxidative-amidation activity to produce an unnatural S-acetamide derivative of lincosamide.
PURPOSE: Dual velocity encoding PC-MRI can produce spurious artifacts when using high ratios of velocity encoding values (VENCs), limiting its ability to generate high-quality images across a wide range of encoding velocities. This study aims to propose and compare dual-VENC correction methods for such artifacts. THEORY AND METHODS: Two denoising approaches based on spatiotemporal regularization are proposed and compared with a state-of-the-art method based on sign correction. Accuracy is assessed using simulated data from an aorta and brain aneurysm, as well as 8 two-dimensional (2D) PC-MRI ascending aorta datasets. Two temporal resolutions (30,60) ms and noise levels (9,12) dB are considered, with noise added to the complex magnetization. The error is evaluated with respect to the noise-free measurement in the synthetic case and to the unwrapped image without additional noise in the volunteer datasets. RESULTS: In all studied cases, the proposed methods are more accurate than the Sign Correction technique. Using simulated 2D+T data from the aorta (60 ms, 9 dB), the Dual-VENC (DV) error 0.82±0.07$$ 0.82\pm 0.07 $$ is reduced to: 0.66±0.04$$ 0.66\pm 0.04 $$ (Sign Correction); 0.34±0.04$$ 0.34\pm 0.04 $$ and 0.32±0.04$$ 0.32\pm 0.04 $$ (proposed techniques). The methods are found to be significantly different (p-value <0.05$$ <0.05 $$ ). Importantly, brain aneurysm data revealed that the Sign Correction method is not suitable, as it increases error when the flow is not unidirectional. All three methods improve the accuracy of in vivo data. CONCLUSION: The newly proposed methods outperform the Sign Correction method in improving dual-VENC PC-MRI images. Among them, the approach based on temporal differences has shown the highest accuracy.
- MeSH
- Algorithms * MeSH
- Aorta * diagnostic imaging MeSH
- Artifacts * MeSH
- Phantoms, Imaging MeSH
- Image Interpretation, Computer-Assisted methods MeSH
- Intracranial Aneurysm diagnostic imaging MeSH
- Humans MeSH
- Magnetic Resonance Imaging * methods MeSH
- Brain diagnostic imaging MeSH
- Computer Simulation MeSH
- Image Processing, Computer-Assisted * methods MeSH
- Signal-To-Noise Ratio * MeSH
- Reproducibility of Results MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
L eishmaniasis is a prevalent disease that impacts 98 countries and territories, mainly in Africa, Asia, and South America. It can cause substantial illness and death, particularly in its visceral manifestation that can be specifically targeted in the development of medications to combat leishmaniasis. This study has found natural compounds with possible inhibitory activity against APX using a reliable and accurate QSAR model. Despite the severe side effects of current treatments and the absence of an effective vaccination, these compounds show promise as a potential treatment for the disease. Nine hit compounds were found, and subsequent molecular docking was performed. Estradiol cypionate showed the lowest binding energy (- 10.5 kcal/mol), thus showing the strongest binding, and also had the strongest binding affinity, with a ΔGTotal of - 26.31 ± 3.01 kcal/mol, second only to the control molecule. Additionally, three hits viz. cloxacillin-sodium (- 16.57 ± 2.89 kcal/mol), cinchonidine (- 16.04 ± 3.27 kcal/mol), and quinine hydrochloride dihydrate (13.38 ± 1.06 kcal/mol) also showed significant binding affinity. Multiple interactions between drugs and active site residues demonstrated a substantial binding affinity with the target protein. The identified compounds exhibited drug-like effects and were orally bioavailable based on their ADME-toxicology features. Overall, estradiol cypionate, cloxacillin sodium, cinchonidine, and quinine hydrochloride dihydrate all exhibited inhibitory effects on the APX enzyme of Leishmania donovani. These results suggest that further investigation is needed to explore the potential of developing novel anti-leishmaniasis drugs using these compounds.
- MeSH
- Antiprotozoal Agents * pharmacology chemistry MeSH
- Enzyme Inhibitors * pharmacology chemistry MeSH
- Quantitative Structure-Activity Relationship MeSH
- Leishmaniasis * drug therapy MeSH
- Humans MeSH
- Molecular Docking Simulation MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
OBJECTIVE: Resection of the vestibular schwannoma causes acute peripheral vestibular loss. The process of central compensation starts immediately afterward. The rehabilitation goal is to support this process and restore the quality of life. MATERIALS AND METHODS: In this prospective single-center study, 67 consecutive patients underwent vestibular schwannoma resection (40 females, mean age 52 ± 12 years). The patients were divided into three groups: the prehabilitation with intratympanic gentamicin group, the virtual reality group (optokinetic stimulation via virtual reality goggles in the first ten days after the surgery), and the control group. All patients were examined with objective methods and completed questionnaires before the prehabilitation, before the surgery, at the hospital discharge, and after three months. RESULTS: Intratympanic gentamicin prehabilitation leads ipsilaterally to a significant aVOR reduction in all semicircular canals (p < 0.050), the increase of the unilateral weakness in air calorics (p = 0.026), and loss of cVEMPs responses (p = 0.017). Prehabilitation and postoperative exposure to virtual reality scenes improved the patient's perception of vertigo problems according to Dizziness Handicap Inventory (p = 0.039 and p = 0.076, respectively). These findings conform with the optokinetic testing results, which showed higher slow phase velocities at higher speeds (40 deg/s) in both targeted groups compared to the control group. CONCLUSION: Preoperative intratympanic gentamicin positively affects peripheral vestibular function, influencing balance perception after VS resection. In long-term follow-up, prehabilitation and postoperative exposure to virtual reality improve patients' quality of life in the field of vertigo problems.
- MeSH
- Anti-Bacterial Agents administration & dosage MeSH
- Adult MeSH
- Gentamicins * administration & dosage MeSH
- Injection, Intratympanic MeSH
- Quality of Life MeSH
- Middle Aged MeSH
- Humans MeSH
- Postoperative Care methods MeSH
- Preoperative Care methods MeSH
- Prospective Studies MeSH
- Aged MeSH
- Virtual Reality Exposure Therapy methods MeSH
- Vestibular Function Tests MeSH
- Neuroma, Acoustic * surgery MeSH
- Virtual Reality MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.
- MeSH
- Apoptosis * drug effects MeSH
- Cell Cycle drug effects MeSH
- Histone Deacetylases metabolism MeSH
- Histone Deacetylase Inhibitors * pharmacology chemical synthesis chemistry MeSH
- Hydroxamic Acids * pharmacology chemical synthesis chemistry MeSH
- Coumaric Acids * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents * pharmacology chemical synthesis chemistry MeSH
- Drug Screening Assays, Antitumor MeSH
- Molecular Docking Simulation MeSH
- THP-1 Cells MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
This study presents a combined experimental and numerical investigation of fiber transport and deposition in a realistic model of the female respiratory tract, extending to the seventh generation of branching. Numerical simulations were performed using the Euler-Lagrange Euler-Rotation (ELER) method, an efficient alternative to conventional Finite Volume Methods that benefits from explicit formulation and vast scalability, enabling fast parallelization on high-performance clusters. The ELER method was coupled with the Lattice Boltzmann Method (LBM) to simulate fiber dynamics under a realistic inspiratory flow profile. Experimental validation was conducted using an identical physical airway replica. The results demonstrated good agreement between simulations and experiments in the upper airways and trachea, with some discrepancies in the bifurcations, likely owing to the challenges of modeling complex turbulent flow with ELER. This method is more accurate than corresponding effective diameter simulations. Deposition patterns were analyzed as a function of fiber dimensions, revealing higher accuracy of the ELER method for smaller particles and confirming the tendency of higher aspect ratio fibers to penetrate deeper into the lungs. The orientation-dependent deposition mechanism was deployed, underscoring the importance of solving the actual orientations of the fibers. While advancing our understanding of fiber transport in female airways, the findings also reveal limitations in current numerical techniques, particularly in bifurcations. This study emphasizes the distinct behavior of fibrous versus spherical particles, with fibers exhibiting a greater propensity to reach deeper lung regions, which has significant implications for inhalation toxicology and drug delivery.
- MeSH
- Administration, Inhalation MeSH
- Models, Biological * MeSH
- Respiratory System * MeSH
- Humans MeSH
- Lung MeSH
- Computer Simulation MeSH
- Trachea * physiology MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Integral membrane proteins carry out essential functions in the cell, and their activities are often modulated by specific protein-lipid interactions in the membrane. Here, we elucidate the intricate role of cardiolipin (CDL), a regulatory lipid, as a stabilizer of membrane proteins and their complexes. Using the in silico-designed model protein TMHC4_R (ROCKET) as a scaffold, we employ a combination of molecular dynamics simulations and native mass spectrometry to explore the protein features that facilitate preferential lipid interactions and mediate stabilization. We find that the spatial arrangement of positively charged residues as well as local conformational flexibility are factors that distinguish stabilizing from non-stabilizing CDL interactions. However, we also find that even in this controlled, artificial system, a clear-cut distinction between binding and stabilization is difficult to attain, revealing that overlapping lipid contacts can partially compensate for the effects of binding site mutations. Extending our insights to naturally occurring proteins, we identify a stabilizing CDL site within the E. coli rhomboid intramembrane protease GlpG and uncover its regulatory influence on enzyme substrate preference. In this work, we establish a framework for engineering functional lipid interactions, paving the way for the design of proteins with membrane-specific properties or functions.
- MeSH
- DNA-Binding Proteins MeSH
- Endopeptidases metabolism chemistry genetics MeSH
- Escherichia coli metabolism genetics MeSH
- Cardiolipins * metabolism chemistry MeSH
- Membrane Proteins * metabolism chemistry genetics MeSH
- Protein Engineering * MeSH
- Escherichia coli Proteins * metabolism chemistry genetics MeSH
- Molecular Dynamics Simulation MeSH
- Protein Binding MeSH
- Publication type
- Journal Article MeSH
Chalcones, potential anticancer agents, have shown promise in the suppression of multidrug resistance due to the inhibition of drug efflux driven by certain adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The gene and protein expression of chosen ABC transporters (multidrug resistance protein 1, ABCB1; multidrug resistance-associated protein 1, ABCC1; and breast cancer resistance protein, ABCG2) in human colorectal cancer cells (COLO 205 and COLO 320, which overexpress active ABCB1) was mainly studied in this work under the influence of a novel synthetic acridine-based chalcone, 1C. While gene expression dropped just at 24 h, compound 1C selectively suppressed colorectal cancer cell growth and greatly lowered ABCB1 protein levels in COLO 320 cells at 24, 48, and 72 h. It also reduced ABCC1 protein levels after 48 h. Molecular docking and ATPase tests show that 1C probably acts as an allosteric modulator of ABCB1. It also lowered galectin-1 (GAL1) expression in COLO 205 cells at 24 h. Functional tests on COLO cells revealed ABCB1 and ABCC1/2 to be major contributors to multidrug resistance in both. Overall, 1C transiently lowered GAL1 in COLO 205 while affecting important functional ABC transporters, mostly ABCB1 and to a lesser extent ABCC1 in COLO 320 cells. COLO 320's absence of GAL1 expression points to a possible yet unknown interaction between GAL1 and ABCB1.
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism MeSH
- ATP-Binding Cassette Transporters * metabolism chemistry genetics MeSH
- Acridines * chemistry pharmacology MeSH
- Chalcone * pharmacology chemistry MeSH
- Chalcones * pharmacology chemistry MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Colorectal Neoplasms metabolism drug therapy MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- ATP Binding Cassette Transporter, Subfamily B metabolism genetics MeSH
- Cell Proliferation drug effects MeSH
- Multidrug Resistance-Associated Protein 2 MeSH
- Multidrug Resistance-Associated Proteins metabolism genetics MeSH
- Antineoplastic Agents * pharmacology chemistry MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- Molecular Docking Simulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Mixed reality technology and three-dimensional (3D) printing are becoming more and morecommon in the field of medicine. During the COVID-19 pandemic and immediately after the restrictions had beeneased, many innovations were implemented in the teaching of future doctors. There was also interest in immersive techniques and 3D printing technology in anatomy teaching. However, these are not common implementations. In 2023, 3D prints and holograms in mixed reality technology were prepared for classes focused on the structure of the heart. They were used to teach students, who, with the support of engineers, could learn about the detailed structure of the heart and familiarize themselves with the new technologies that support the traditional model of learning on human cadavers. Students findthis possibility to be highly valuable. The article presents the process of preparing materials for classes and further implementation possibilities. The authors see an opportunity for the development of the presented technologies in students'teaching at various levels of education and the justification for increasingly widespread implementation.
- MeSH
- Printing, Three-Dimensional * MeSH
- Anatomy * education MeSH
- Augmented Reality * MeSH
- COVID-19 MeSH
- Humans MeSH
- Heart * anatomy & histology MeSH
- Teaching MeSH
- Check Tag
- Humans MeSH
- Publication type
- Video-Audio Media MeSH
- Journal Article MeSH
This paper presents an innovative mathematical model for assessing the dynamics and optimal control of Nipah virus (NiV) with imperfect vaccination. The model formulation considers transmissions through contaminated food and human-to-human contacts. It also incorporates the potential virus transmission through contact with a deceased body infected with NiV. Initially, the NiV model is assessed theoretically, identifying three distinct equilibrium states: the NiV-endemic equilibrium state, the NiV-free equilibrium state, and the equilibrium state involving infected flying foxes. Furthermore, the stability results of the model in the case of constant controls are thoroughly analyzed at the NiV-free equilibrium. Some of the parameters of the model are estimated based on the infected cases documented in Bangladesh from 2001 to 2017. We further perform sensitivity analysis to determine the most influential parameters and formulate effective time-dependent controls. Numerical simulations indicate the optimal course of action for eradicating the disease and provide a comparative analysis of controlling the infection under constant and time-varying interventions. The simulation confirms that the implementation of time-varying interventions is effective in minimizing disease incidence.
- MeSH
- Henipavirus Infections * transmission prevention & control epidemiology MeSH
- Humans MeSH
- Computer Simulation MeSH
- Models, Theoretical MeSH
- Vaccination * MeSH
- Nipah Virus * immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Bangladesh MeSH
