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Research (Washington, D.C.) 20244,4-Dimethylsterols constitute a unique class of phytosterols responsible for regulating endogenous cannabinoid system (ECS) functions. However, precise mechanism...
4,4-Dimethylsterols constitute a unique class of phytosterols responsible for regulating endogenous cannabinoid system (ECS) functions. However, precise mechanism through which 4,4-dimethylsterols affect fat metabolism and the linkage to the ECS remain unresolved. In this study, we identified that 4,4-dimethylsterols, distinct from 4-demethseterols, act as inhibitors of fatty acid amide hydrolases (FAAHs) both in vivo and in vitro. Genetic ablation of FAAHs () abolishes the effects of 4,4-dimethylsterols on fat accumulation and locomotion behavior in a model. We confirmed that dietary intervention with 4,4-dimethylsterols in a high-fat diet (HFD) mouse model leads to a significant reduction in body weight (>11.28%) with improved lipid profiles in the liver and adipose tissues and increased fecal triacylglycerol excretion. Untargeted and targeted metabolomics further verified that 4,4-dimethylsterols influence unsaturated fatty acid biosynthesis and elevate oleoyl ethanolamine levels in the intestine. We propose a potential molecular mechanism in which 4,4-dimethylsterols engage in binding interactions with the catalytic pocket (Ser241) of FAAH-1 protein due to the shielded polarity, arising from the presence of 2 additional methyl groups (CH). Consequently, 4,4-dimethylsterols represent an unexplored class of beneficial phytosterols that coordinate with FAAH-1 activity to reduce fat accumulation, which offers new insight into intervention strategies for treating diet-induced obesity.
PubMed: 38812531
DOI: 10.34133/research.0377 -
Journal of Integrative Neuroscience Apr 2024Magnetoencephalography (MEG) is a non-invasive imaging technique for directly measuring the external magnetic field generated from synchronously activated pyramidal...
BACKGROUND
Magnetoencephalography (MEG) is a non-invasive imaging technique for directly measuring the external magnetic field generated from synchronously activated pyramidal neurons in the brain. The optically pumped magnetometer (OPM) is known for its less expensive, non-cryogenic, movable and user-friendly custom-design provides the potential for a change in functional neuroimaging based on MEG.
METHODS
An array of OPMs covering the opposite sides of a subject's head is placed inside a magnetically shielded room (MSR) and responses evoked from the auditory cortices are measured.
RESULTS
High signal-to-noise ratio auditory evoked response fields (AEFs) were detected by a wearable OPM-MEG system in a MSR, for which a flexible helmet was specially designed to minimize the sensor-to-head distance, along with a set of bi-planar coils developed for background field and gradient nulling. Neuronal current sources activated in AEF experiments were localized and the auditory cortices showed the highest activities. Performance of the hybrid optically pumped magnetometer-magnetoencephalography/electroencephalography (OPM-MEG/EEG) system was also assessed.
CONCLUSIONS
The multi-channel OPM-MEG system performs well in a custom built MSR equipped with bi-planar coils and detects human AEFs with a flexible helmet. Moreover, the similarities and differences of auditory evoked potentials (AEPs) and AEFs are discussed, while the operation of OPM-MEG sensors in conjunction with EEG electrodes provides an encouraging combination for the exploration of hybrid OPM-MEG/EEG systems.
Topics: Humans; Magnetoencephalography; Evoked Potentials, Auditory; Auditory Cortex; Electroencephalography; Adult; Male
PubMed: 38812381
DOI: 10.31083/j.jin2305093 -
Scientific Reports May 2024Quantum technologies play a pivotal role in driving transformative advancements across diverse fields, surpassing classical approaches and empowering us to address...
Quantum technologies play a pivotal role in driving transformative advancements across diverse fields, surpassing classical approaches and empowering us to address complex challenges more effectively; however, the need for ultra-low temperatures limits the use of these technologies to particular fields. This work comes to alleviate this problem. We present a way of phononic bandgap engineering using FEM by which the radiative mechanical energy dissipation of a nanomechanical oscillator can be significantly suppressed through coupling with a complementary oscillating mode of a defect of the surrounding phononic crystal (PnC). Applied to an optomechanically coupled nanobeam resonator in the megahertz regime, we find a mechanical quality factor improvement of up to four orders of magnitude compared to conventional PnC designs. As this method is based on geometrical optimization of the PnC and frequency matching of the resonator and defect mode, it is applicable to a wide range of resonator types and frequency ranges. Taking advantage of the, hereinafter referred to as, "regenerative coupling" in phononic crystals, the presented device is capable of reaching f × Q products exceeding 10E16 Hz with only two rows of PnC shield. Thus, stable quantum states with mechanical decoherence times up to 700 μs at room temperature can be obtained, offering new opportunities for the optimization of mechanical resonator performance and advancing the room temperature quantum field across diverse applications.
PubMed: 38811848
DOI: 10.1038/s41598-024-63199-1 -
Scientific Reports May 2024Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for treating cancers. This method consists in modifying the patients' T-cells to directly...
Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for treating cancers. This method consists in modifying the patients' T-cells to directly target antigen-presenting cancer cells. One of the barriers to the development of this type of therapies, is target antigen heterogeneity. It is thought that intratumour heterogeneity is one of the leading determinants of therapeutic resistance and treatment failure. While understanding antigen heterogeneity is important for effective therapeutics, a good therapy strategy could enhance the therapy efficiency. In this work we introduce an agent-based model (ABM), built upon a previous ABM, to rationalise the outcomes of different CAR T-cells therapies strategies over heterogeneous tumour-derived organoids. We found that one dose of CAR T-cell therapy should be expected to reduce the tumour size as well as its growth rate, however it may not be enough to completely eliminate it. Moreover, the amount of free CAR T-cells (i.e. CAR T-cells that did not kill any cancer cell) increases as we increase the dosage, and so does the risk of side effects. We tested different strategies to enhance smaller dosages, such as enhancing the CAR T-cells long-term persistence and multiple dosing. For both approaches an appropriate dosimetry strategy is necessary to produce "effective yet safe" therapeutic results. Moreover, an interesting emergent phenomenon results from the simulations, namely the formation of a shield-like structure of cells with low antigen expression. This shield turns out to protect cells with high antigen expression. Finally we tested a multi-antigen recognition therapy to overcome antigen escape and heterogeneity. Our studies suggest that larger dosages can completely eliminate the organoid, however the multi-antigen recognition increases the risk of side effects. Therefore, an appropriate small dosages dosimetry strategy is necessary to improve the outcomes. Based on our results, it is clear that a proper therapeutic strategy could enhance the therapies outcomes. In that direction, our computational approach provides a framework to model treatment combinations in different scenarios and to explore the characteristics of successful and unsuccessful treatments.
Topics: Humans; Organoids; Immunotherapy, Adoptive; Computer Simulation; Neoplasms; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 38811838
DOI: 10.1038/s41598-024-63125-5 -
Molecular Pharmacology May 2024Melatonin -acetyl-5-methoxytriptamine is an ancient molecule which synchronizes the internal biological activity with the environmental photoperiod. It is synthesized by...
Melatonin -acetyl-5-methoxytriptamine is an ancient molecule which synchronizes the internal biological activity with the environmental photoperiod. It is synthesized by the pineal gland during the night and released to the general circulation where it reaches nanomolar concentrations. The indolamine acts through melatonin receptors and binds to nearly 18 different proteins. Among these is calmodulin, a phylogenetically conserved protein which is the main transductor of the calcium signaling. In this review, we will describe evidence in support that melatonin binds to calmodulin in presence of calcium, as well as the implications in the activity of Calmodulin kinase II as an antagonist and stimulating its activity. Also, we review literature that support the relevance on melatonin binding to calmodulin in the regulation of circadian rhythms in unicellular organisms, as well as in neuronal development in mammals as an ancient conserved mechanism. Finally, it is remarked the importance of antioxidant effects of melatonin on calmodulin preservation. This review compiled evidence in support that melatonin binds to calmodulin. We discuss the dual effect of melatonin on the activity of CaM binding proteins, the possible mechanisms involved and the relevance on regulation of circadian rhythms. Finally, we describe evidence in support that binding of melatonin to CaM hydrophobic pockets may prevent the oxidation of methionine species through a shielding effect, in addition to its antioxidant capabilities, preserving the functionality of CaM.
PubMed: 38811168
DOI: 10.1124/molpharm.123.000812 -
RSC Advances May 2024The von Hippel-Lindau (VHL) protein serves as the substrate recognition subunit of the multi-subunit Cullin-2 RING E3 ubiquitin ligase (CRL2), which regulates...
The von Hippel-Lindau (VHL) protein serves as the substrate recognition subunit of the multi-subunit Cullin-2 RING E3 ubiquitin ligase (CRL2), which regulates intracellular concentrations of hypoxia inducible factors (HIFs) through a ubiquitin proteasome system (UPS) cascade. Strategic recruitment of CRL2 by bi- or trifunctional targeted protein degraders (, PROTACs®) offers the prospect of promoting aberrant polyubiquitination and ensuing proteasomal degradation of disease-related proteins. Non-peptidic, l-hydroxyproline-bearing VHL ligands such as VH032 (1) and its chiral benzylic amine analog Me-VH032 (2), are functional components of targeted protein degraders commonly employed for this purpose. Herein, we compare two approaches for the preparation of 1 and 2 primarily highlighting performance differences between Pd(OAc) and Pd-PEPPSI-IPr for the key C-H arylation of 4-methylthiazole. Results from this comparison prompted the development of a unified, five-step route for the preparation of either VH032 (1) or Me-VH032 (2) in multigram quantities, resulting in yields of 56% and 61% for 1 and 2, respectively. Application of -Boc-l-4-hydroxyproline rather than -butoxycarbonyl to shield the benzylic amine during the coupling step enhances step economy. Additionally, we identified previously undisclosed minor byproducts generated during arylation steps along with observations from amine deprotection and amidation reaction steps that may prove helpful not only for the preparation of 1 and 2, but for other VHL recruiting ligands, as well.
PubMed: 38808246
DOI: 10.1039/d4ra01974a -
Bioactive Materials Sep 2024Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even...
Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even life-threatening consequences. Amifostine (AMF) is a validated radioprotectant extensively applied in radiation and chemotherapy medicine, but the short half-life limits its bioavailability and clinical applications, remaining as a great challenge to be addressed. DNA-assembled nanostructures especially the tetrahedral framework nucleic acids (tFNAs) are promising nanocarriers with preeminent biosafety, low biotoxicity, and high transport efficiency. The tFNAs also have a relative long-term maintenance for structural stability and excellent endocytosis capacity. We therefore synthesized a tFNA-based delivery system of AMF for multi-organ radioprotection (tFNAs@AMF, also termed nanosuit). By establishing the mice models of accidental total body irradiation (TBI) and radiotherapy model of Lewis lung cancer, we demonstrated that the nanosuit could shield normal cells from IR-induced DNA damage by regulating the molecular biomarkers of anti-apoptosis and anti-oxidative stress. In the accidental total body irradiation (TBI) mice model, the nanosuit pretreated mice exhibited satisfactory alteration of superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents, and functional recovery of hematopoietic system, reducing IR-induced pathological damages of multi-organ and safeguarding mice from lethal radiation. More importantly, the nanosuit showed a selective radioprotection of the normal organs without interferences of tumor control in the radiotherapy model of Lewis lung cancer. Based on a conveniently available DNA tetrahedron-based nanocarrier, this work presents a high-efficiency delivery system of AMF with the prolonged half-life and enhanced radioprotection for multi-organs. Such nanosuit pioneers a promising strategy with great clinical translation potential for radioactivity protection.
PubMed: 38808157
DOI: 10.1016/j.bioactmat.2024.05.017 -
Sisli Etfal Hastanesi Tip Bulteni 2024Pseudoaneurysm (PA) and carotid cavernous fistula (CCF) of the internal carotid artery (ICA) is an uncommon complication of endoscopic endonasal surgery that occurs in...
Pseudoaneurysm (PA) and carotid cavernous fistula (CCF) of the internal carotid artery (ICA) is an uncommon complication of endoscopic endonasal surgery that occurs in 1% of cases. We report on the successful placement of flow-diverting stents (FDS) to ICA pseudoaneurysm and caroticocavernous fistula caused by iatrogenic ICA injury for a pituitary adenoma in a 37-year-old female. After placement of the pipeline shield given a certain time, dual antiplatelet agents (DAPT) and follow-up angiogram verified complete aneurysm obliteration and effective endoluminal reconstruction of the injured vessel. In managing ICA pseudoaneurysms, the placement of flow-diverting stents is a viable vessel-sparing technique.
PubMed: 38808057
DOI: 10.14744/SEMB.2024.84479 -
Cureus Apr 2024One of the leading environmental hazards, ionizing radiation, is linked to several detrimental health consequences in the body. RADPAD (Worldwide Innovations &... (Review)
Review
Assessing the Efficacy of RADPAD Protection Drape in Reducing Radiation Exposure to Operators in the Cardiac Catheterization Laboratory: A Systematic Review and Meta-Analysis.
One of the leading environmental hazards, ionizing radiation, is linked to several detrimental health consequences in the body. RADPAD (Worldwide Innovations & Technologies, Inc., Kansas City, Kansas) is a sterile, lead-free, lightweight, disposable radiation protection shield. We conducted a systematic review and meta-analysis to determine the effectiveness of RADPAD protection drapes in the cardiac catheterization lab and how they can aid interventional cardiologists in becoming subjected to less scatter radiation. PubMed, Embase, and Google Scholar were searched for studies discussing the efficacy of RADPAD protection drapes in reducing radiation exposure to operators in the cardiac catheterization laboratory. A random-effects model was used to pool odds ratios (ORs) and 95% confidence intervals (CIs) for endpoints: primary operator exposure dose, dose area product (DAP), relative exposure, and screening time. Our analysis included 892 patients from six studies. Compared to the No-RADPAD group, primary operator exposure dose (E) was significantly lower in the RADPAD group (OR: -0.9, 95% CI: -1.36 to -0.43, I= 80.5%, p = 0.0001). DAP was comparable between both groups (OR: 0.008, 95% CI: -0.12 to -0.14, I= 0%, p = 0.9066). There was no difference in the relative exposure (E/DAP) (OR: -0.47, 95% CI: -0.96 to 0.02, I= 0%, p = 0.90) and screening time (OR: 0.13, 95% CI: 0.08 to 0.35, I= 0%, p = 0.22) between the two groups. The interventional cardiology laboratory is exposed to significantly less scatter radiation during procedures owing to the RADPAD protective drape. Consequently, all catheterization laboratories could be advised to employ RADPAD protective drapes.
PubMed: 38807800
DOI: 10.7759/cureus.59215 -
Scientific Reports May 2024Stress shielding and aseptic loosening are complications of short stem total hip arthroplasty, which may lead to hardware failure. Stems with increased porosity toward...
Stress shielding and aseptic loosening are complications of short stem total hip arthroplasty, which may lead to hardware failure. Stems with increased porosity toward the distal end were discovered to be effective in reducing stress shielding, however, there is a lack of research on optimized porous distribution in stem's coating. This study aimed to optimize the distribution of the coefficient of friction of a metaphyseal femoral stem, aiming for reducing stress shielding in the proximal area. A finite element analysis model of an implanted, titanium alloy short-tapered wedge stem featuring a porous coating made of titanium was designed to simulate a static structural analysis of the femoral stem's behavior under axial loading in Analysis System Mechanical Software. For computational feasibility, 500 combinations of coefficients of friction were randomly sampled. Increased strains in proximal femur were found in 8.4% of the models, which had decreased coefficients of friction in middle medial areas of porous coating and increased in lateral proximal and lateral and medial distal areas. This study reported the importance of the interface between bone and middle medial and distal lateral areas of the porous coating in influencing the biomechanical behavior of the proximal femur, and potentially reducing stress shielding.
Topics: Humans; Friction; Femur; Hip Prosthesis; Porosity; Arthroplasty, Replacement, Hip; Finite Element Analysis; Titanium; Stress, Mechanical; Prosthesis Design; Coated Materials, Biocompatible; Biomechanical Phenomena; Alloys
PubMed: 38806607
DOI: 10.1038/s41598-024-63077-w