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Journal of Chemical Theory and... Jun 2024The optimal interaction of drugs with plasma membranes and membranes of subcellular organelles is a prerequisite for desirable pharmacology. Importantly, for drugs...
Application of Generative Artificial Intelligence in Predicting Membrane Partitioning of Drugs: Combining Denoising Diffusion Probabilistic Models and MD Simulations Reduces the Computational Cost to One-Third.
The optimal interaction of drugs with plasma membranes and membranes of subcellular organelles is a prerequisite for desirable pharmacology. Importantly, for drugs targeting the transmembrane lipid-facing sites of integral membrane proteins, the relative affinity of a drug to the bilayer lipids compared to the surrounding aqueous phase affects the partitioning, access, and binding of the drug to the target site. Molecular dynamics (MD) simulations, including enhanced sampling techniques such as steered MD, umbrella sampling (US), and metadynamics, offer valuable insights into the interactions of drugs with the membrane lipids and water in atomistic detail. However, these methods are computationally prohibitive for the high-throughput screening of drug candidates. This study shows that applying denoising diffusion probabilistic models (DDPMs), a generative AI method, to US simulation data reduces the computational cost significantly. Specifically, the models used only partial (one-third) data from the US simulations and reproduced the complete potential of mean force (PMF) profiles for three FDA-approved drugs (β2-adrenergic agonists) and ∼20 biologically relevant chemicals with known experimentally characterized bilayer locations. Intriguingly, the model can predict the solvation-free energies for partitioning and crossing the bilayer, preferred bilayer locations (low-energy well), and orientations of the ligands with high accuracy. The results indicate that DDPMs can be used to characterize the complete membrane partitioning profile of drug molecules using fewer umbrella sampling simulations at select positions along the bilayer normal (-axis), irrespective of their amphiphilic-lipophilic-cephalophilic characteristics.
PubMed: 38942732
DOI: 10.1021/acs.jctc.4c00315 -
International Journal of Biological... Jun 2024Controlled drug delivery systems offer numerous advantages. This research evaluates Opuntia leaf mucilage grafted with polyacrylamide (OPM-g-PAM) as a promising...
Evaluation of microwave irradiated Polyacrylamide grafted Opuntia leaf mucilage graft copolymer (OPM-g-PAM) as effective controlled release polymer for release of Rosuvastastin as model drug.
Controlled drug delivery systems offer numerous advantages. This research evaluates Opuntia leaf mucilage grafted with polyacrylamide (OPM-g-PAM) as a promising controlled-release polymer. PAM chains were grafted onto the backbone of OPM using a microwave-assisted method. Optimization of the best grade was based on % grafting efficiency and intrinsic viscosity, followed by extensive physical and analytical characterizations. Analytical characterizations revealed semicrystalline nature of the biomaterial. SEM and AFM observations revealed rough and porous surfaces, indicating effective grafting. Swelling behavior showed maximum sensitivity at pH 7, with reduced swelling at higher sodium chloride concentrations. A comparative study of % drug release of Rosuvastatin over 24 h showed that the optimized grade controlled drug release effectively, achieving 78.5 % release compared to 98.8 % for GF-3. The release data fitted the Korsmeyer-Peppas model, with an "n" value of 0.8334, indicating non-Fickian (anomalous) diffusion. Bacterial biodegradability studies confirmed the high biodegradability of the graft copolymer. In vitro acute toxicity tests showed no toxicity, as confirmed by histopathological studies of heart, liver, and kidney. Overall, the results indicate that OPM-g-PAM is a highly promising material for use in drug delivery systems, demonstrating potential as a novel controlled-release polymer.
PubMed: 38942673
DOI: 10.1016/j.ijbiomac.2024.133200 -
Neuroimaging Clinics of North America Aug 2024Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease of the central nervous system, commonly featuring disability and cognitive impairment. The... (Review)
Review
Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease of the central nervous system, commonly featuring disability and cognitive impairment. The pathologic hallmark of MS lies in demyelination and hence impaired structural and functional neuronal pathways. Recent studies have shown that MS shows extensive structural disconnection of key network hub areas like the thalamus, combined with a functional network reorganization that can mostly be related to poorer clinical functioning. As MS can, therefore, be considered a network disorder, this review outlines recent innovations in the field of network neuroscience in MS.
Topics: Humans; Multiple Sclerosis; Brain; Nerve Net; Magnetic Resonance Imaging; Neuroimaging
PubMed: 38942522
DOI: 10.1016/j.nic.2024.03.008 -
Neuroimaging Clinics of North America Aug 2024In recent decades, advances in neuroimaging have profoundly transformed our comprehension of central nervous system demyelinating diseases. Remarkable technological... (Review)
Review
In recent decades, advances in neuroimaging have profoundly transformed our comprehension of central nervous system demyelinating diseases. Remarkable technological progress has enabled the integration of cutting-edge acquisition and postprocessing techniques, proving instrumental in characterizing subtle focal changes, diffuse microstructural alterations, and macroscopic pathologic processes. This review delves into state-of-the-art modalities applied to multiple sclerosis, neuromyelitis optica spectrum disorders, and myelin oligodendrocyte glycoprotein antibody-associated disease. Furthermore, it explores how this dynamic landscape holds significant promise for the development of effective and personalized clinical management strategies, encompassing support for differential diagnosis, prognosis, monitoring treatment response, and patient stratification.
Topics: Humans; Neuroimaging; Brain; Demyelinating Diseases; Neuromyelitis Optica; Magnetic Resonance Imaging; Multiple Sclerosis
PubMed: 38942520
DOI: 10.1016/j.nic.2024.03.003 -
Cognitive Neuropsychology Jun 2024We present a case study detailing cognitive performance, functional neuroimaging, and effects of a hypothesis-driven treatment in a 10-year-old girl diagnosed with...
We present a case study detailing cognitive performance, functional neuroimaging, and effects of a hypothesis-driven treatment in a 10-year-old girl diagnosed with complete, isolated corpus callosum agenesis. Despite having average overall intellectual abilities, the girl exhibited profound surface dyslexia and dysgraphia. Spelling treatment significantly and persistently improved her spelling of trained irregular words, and this improvement generalized to reading accuracy and speed of trained words. Diffusion weighted imaging revealed strengthened intrahemispheric white matter connectivity of the left temporal cortex after treatment and identified interhemispheric connectivity between the occipital lobes, likely facilitated by a pathway crossing the midline via the posterior commissure. This case underlines the corpus callosum's critical role in lexical reading and writing. It demonstrates that spelling treatment may enhance interhemispheric connectivity in corpus callosum agenesis through alternative pathways, boosting the development of a more efficient functional organization of the visual word form area within the left temporo-occipital cortex.
PubMed: 38942485
DOI: 10.1080/02643294.2024.2368876 -
Korean Journal of Radiology Jul 2024This study systematically reviewed the role of diffusion-weighted imaging (DWI) in the assessment of molecular prognostic biomarkers in breast cancer, focusing on the... (Meta-Analysis)
Meta-Analysis Review
This study systematically reviewed the role of diffusion-weighted imaging (DWI) in the assessment of molecular prognostic biomarkers in breast cancer, focusing on the correlation of apparent diffusion coefficient (ADC) with hormone receptor status and prognostic biomarkers. Our meta-analysis includes data from 52 studies examining ADC values in relation to estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67 status. The results indicated significant differences in ADC values among different receptor statuses, with ER-positive, PgR-positive, HER2-negative, and Ki-67-positive tumors having lower ADC values compared to their negative counterparts. This study also highlights the potential of advanced DWI techniques such as intravoxel incoherent motion and non-Gaussian DWI to provide additional insights beyond ADC. Despite these promising findings, the high heterogeneity among the studies underscores the need for standardized DWI protocols to improve their clinical utility in breast cancer management.
Topics: Humans; Breast Neoplasms; Diffusion Magnetic Resonance Imaging; Female; Biomarkers, Tumor; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Ki-67 Antigen
PubMed: 38942456
DOI: 10.3348/kjr.2023.1188 -
International Journal of Biological... Jun 2024Thiosulfate has been considered as a more environmentally-friendly alternative to cyanide salts for the extraction of gold from gold ores and the development of...
Thiosulfate has been considered as a more environmentally-friendly alternative to cyanide salts for the extraction of gold from gold ores and the development of affordable, green and efficient adsorbents for the isolation of gold-thiosulfate complex (Au(SO)) from the leaching solution remains a significant challenge. To address this issue, chitosan, a natural macromolecule, was selected as a carrier and chemically modified with ionic liquids. The ionic liquids modified chitosan showed greater adsorption capacity towards Au(SO) compared with pristine chitosan. The adsorption of Au(SO) on ionic liquid modified chitosan followed Freundlich isotherm and pseudo-second order kinetic models, involving an anion-exchange mechanism with liquid film diffusion as the rate-limiting step. The chitosan modified with butylimidazolium-based ionic liquid modified had an adsorption capacity of 5.0 mg g for Au(SO) (10 mg L, pH 6, 2 g L of adsorbent dosage), outperforming other reported adsorbents. The ionic liquid modified chitosan showed a high adsorption efficiency of up to 96.7 % for Au(SO) in an actual thiosulfate leaching solution with a desorption efficiency of 98.4 %, suggesting that the ionic liquid modified chitosan has the potential to be a eco-friendly, biocompatible and effective adsorbent for the recovery of Au(SO).
PubMed: 38942407
DOI: 10.1016/j.ijbiomac.2024.133481 -
The Spine Journal : Official Journal of... Jun 2024Extreme Lateral Interbody Fusion (XLIF) has been established as an effective treatment for degenerative disorders of the lumbar spine. Nevertheless, there is a potential...
BACKGROUND CONTEXT
Extreme Lateral Interbody Fusion (XLIF) has been established as an effective treatment for degenerative disorders of the lumbar spine. Nevertheless, there is a potential risk of lumbar plexus damage associated with XLIF, especially during surgeries at the L4-5 segment. Diffusion Tensor Imaging (DTI) evaluates the directional diffusion of water molecules in tissue, providing a more intricate depiction of internal tissue microstructure compared to conventional MRI techniques. The capability of DTI sequences to elucidate the three-dimensional interplay between lumbar nerve pathways and adjacent musculoskeletal structures, potentially reducing the incidence of nerve injury complications related to XLIF, remains to be established.
PURPOSE
This study evaluates the effectiveness of preoperative Diffusion Tensor Imaging (DTI) in reducing neurological complications after Extreme Lateral Interbody Fusion (XLIF) surgeries at the L4-5 level, focusing on the interaction between lumbar nerves and the psoas major muscle.
STUDY DESIGN
Retrospective case-control study.
PATIENT SAMPLE
The study included 128 patients undergoing XLIF surgery for degenerative disorders at the L4-5 segment: 68 in the traditional group and 62 in the DTI group.
OUTCOME MEASURES
The study assessed Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) scores, along with complication rates. It also documented psoas major muscle morphology and its correlation with nerve pathways.
METHODS
A retrospective analysis of 128 patients undergoing XLIF surgery for degenerative disorders at the L4-5 segment between February 2020 and August 2022 was conducted. The cohort was divided into a traditional group (68 patients) receiving pre-surgery MRI scans to identify surgical entry points at the intervertebral space midpoint (Zones II-III junction) and a DTI group (62 patients) who additionally underwent preoperative DTI to customize entry points. The study evaluated VAS and ODI scores, complication rates, psoas major muscle morphology, and its interaction with nerve pathways.
RESULTS
The traditional group uniformly chose the Zone II-III junction for entry. In contrast, the DTI group's entry points varied. Postoperative follow-up revealed significant improvements in VAS and ODI scores in both groups. However, the DTI group experienced fewer immediate postoperative complications such as thigh pain, numbness, and motor disturbances. The study also noted a ventral shift in nerve positioning in patients with elevated psoas muscles.
CONCLUSIONS
Preoperative DTI effectively maps the relationship between the psoas major muscle and lumbar nerves. Tailoring surgical entry points based on DTI results significantly reduces the risk of nerve damage in XLIF surgeries. The study underscores the importance of recognizing variability in lumbar nerve pathways due to differing psoas muscle morphologies, highlighting a higher risk of nerve injury in patients with elevated psoas muscles during XLIF procedures.
PubMed: 38942298
DOI: 10.1016/j.spinee.2024.06.017 -
Journal of Pharmaceutical Sciences Jun 2024This study aimed to investigate the impact of amorphous solubility and colloidal drug-rich droplets on drug absorption. The amorphous solubility of cilnidipine (CND) in...
This study aimed to investigate the impact of amorphous solubility and colloidal drug-rich droplets on drug absorption. The amorphous solubility of cilnidipine (CND) in AS-HF grade of hypromellose acetate succinate (HPMC-AS) solution was significantly reduced compared to that in non-polymer solution due to AS-HF partitioning into the CND-rich phase. In contrast, AS-LF grade of HPMC-AS has minimal effect on the amorphous solubility. The size of colloidal CND-rich droplets formed in the CND-supersaturated solution was less than 100 nm in the presence of AS-HF, while 200-450 nm in the presence of AS-LF. When the CND concentrations were near the amorphous solubility, CND membrane flux was reduced in the presence of AS-HF due to the decrease in the amorphous solubility of CND. However, the CND flux increased with the increase in CND-rich droplets, especially in the AS-HF solution. The size reduction of the CND-rich droplets led to their effective diffusion into the unstirred water layer, enhancing CND flux. In higher CND concentration regions, the CND flux became higher in the AS-HF solution than in the AS-LF solution. Thus, it is essential to elucidate the drug concentration-dependent impact of the colloidal drug-rich droplets on the drug absorption performance to optimize supersaturating formulations.
PubMed: 38942292
DOI: 10.1016/j.xphs.2024.06.017 -
International Journal of Antimicrobial... Jun 2024Bacteroides fragilis is the most frequent cause of anaerobic bacteraemia. Although recent data suggest a rise in antimicrobial resistance (AMR) of this and other...
BACKGROUND
Bacteroides fragilis is the most frequent cause of anaerobic bacteraemia. Although recent data suggest a rise in antimicrobial resistance (AMR) of this and other anaerobic bacteria, surveillance remains limited due to a lack of both data availability and comparability. However, a newly introduced standardised method for antimicrobial susceptibility testing (AST) of anaerobic bacteria has made larger scale surveillance possible for the first time.
AIM
To investigate phenotypic AMR of Bacteroides fragilis isolates from bacteraemia across Europe in 2022.
METHODS
In a multicentre approach, clinical microbiology laboratories in Europe were invited to contribute results of AST for Bacteroides fragilis blood culture isolates (including only the first isolate per patient and year). AST of a selection of four antibiotics was performed locally by participating laboratories in a prospective or retrospective manner, using the new EUCAST disc diffusion method on fastidious anaerobe agar (FAA-HB).
RESULTS
A total of 16 European countries reported antimicrobial susceptibilities in 449 unique isolates of Bacteroides fragilis from blood cultures in 2022. Clindamycin demonstrated the highest resistance rates (20.9%, range 0 - 63.6%), followed by piperacillin-tazobactam (11.1%, 0 - 54.5%), meropenem (13.4%, 0 - 45.5%), and metronidazole (1.8%, 0 - 20.0%), all with wide variation between countries.
CONCLUSION
Considering that the mean resistance rates across Europe were higher than expected for three of the four anti-anaerobic antibiotics under surveillance, both local AST of clinically relevant isolates of Bacteroides fragilis and continued surveillance on an international level is warranted.
PubMed: 38942247
DOI: 10.1016/j.ijantimicag.2024.107241