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Analytical Chemistry Jun 2024The elucidation of protein-membrane interactions is pivotal for comprehending the mechanisms underlying diverse biological phenomena and membrane-related diseases. In...
The elucidation of protein-membrane interactions is pivotal for comprehending the mechanisms underlying diverse biological phenomena and membrane-related diseases. In this investigation, vacuum-ultraviolet circular dichroism (VUVCD) spectroscopy, utilizing synchrotron radiation (SR), was employed to dynamically observe membrane interaction processes involving water-soluble proteins at the secondary-structure level. The study utilized a time-resolved (TR) T-shaped microfluidic cell, facilitating the rapid and efficient mixing of protein and membrane solutions. This system was instrumental in acquiring measurements of the time-resolved circular dichroism (TRCD) spectra of β-lactoglobulin (bLG) during its interaction with lysoDMPG micelles. The results indicate that bLG undergoes a β-α conformation change, leading to the formation of the membrane-interacting state (M-state), with structural alterations occurring in more than two steps. Global fitting analysis, employing biexponential functions with all of the TRCD spectral data sets, yielded two distinct rate constants (0.18 ± 0.01 and 0.06 ± 0.003/s) and revealed a unique spectrum corresponding to an intermediate state (I-state). Secondary-structure analysis of bLG in its native (N-, I-, and M-states) highlighted that structural changes from the N- to I-states predominantly occurred in the N- and C-terminal regions, which were prominently exposed to the membrane. Meanwhile, transitions from the I- to M-states extended into the inner barrel regions of bLG. Further examination of the physical properties of α-helical segments, such as effective charge and hydrophobicity, revealed that the N- to I- and I- to M-state transitions, which are ascribed to first- and second-rate constants, respectively, are primarily driven by electrostatic and hydrophobic interactions, respectively. These findings underscore the capability of the TR-VUVCD system as a robust tool for characterizing protein-membrane interactions at the molecular level.
PubMed: 38907695
DOI: 10.1021/acs.analchem.4c00556 -
Translational Oncology Jun 2024Radiation-induced lung injury (RILI) is a severe complication arising from thoracic tumor radiotherapy, which constrains the possibility of increasing radiation dosage....
Radiation-induced lung injury (RILI) is a severe complication arising from thoracic tumor radiotherapy, which constrains the possibility of increasing radiation dosage. Current RILI therapies provide only limited relief and may result in undesirable side effects. Therefore, there is an urgent demand for effective and low-toxicity treatments for RILI. Macrophages play a pivotal role in RILI, promoting inflammation in the initial stages and facilitating fibrosis in the later stages. Sodium clodronate, a bisphosphonate, can induce macrophage apoptosis when encapsulated in liposomes. In this study, we explored the potential of liposomal sodium clodronate (LC) as a specific agent for depleting macrophages to alleviate acute RILI. We assessed the impact of LC on macrophage consumption both in vitro and in vivo. In a mouse model of acute RILI, LC treatment group led to a reduction in alveolar macrophage counts, mitigated lung injury severity, and lowered levels of pro-inflammatory cytokines in both plasma and bronchoalveolar lavage fluid. Additionally, we further elucidated the specific effects and mechanism of LC on macrophages in vitro. Alveolar macrophages MHS cells were subjected to varying concentrations of LC (0, 50, 100, 200 μg/ml), and the results demonstrated its dose-dependent inhibition of cell proliferation and induction of apoptosis. Moreover, LC decreased the secretion of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Conditioned media from LC-treated macrophages protected alveolar epithelial cells MLE-12 from radiation-induced damage, as demonstrated by reduced apoptosis and DNA damage. These findings imply that LC-mediated macrophage depletion may present a promising therapeutic strategy for alleviating radiation-induced lung injury.
PubMed: 38906066
DOI: 10.1016/j.tranon.2024.102029 -
Journal of Environmental Radioactivity Jun 2024Methods for determining the radiation dose received by exposed biota require major improvements to reduce uncertainties and increase precision. We share our experiences... (Review)
Review
Methods for determining the radiation dose received by exposed biota require major improvements to reduce uncertainties and increase precision. We share our experiences in attempting to quantify external dose rates to free-ranging wildlife using GPS-coupled dosimetry methods. The manuscript is a primer on fundamental concepts in wildlife dosimetry in which the complexities of quantifying dose rates are highlighted, and lessons learned are presented based on research with wild boar and snakes at Fukushima, wolves at Chornobyl, and reindeer in Norway. GPS-coupled dosimeters produced empirical data to which numerical simulations of external dose using computer software were compared. Our data did not support a standing paradigm in risk analyses: Using averaged soil contaminant levels to model external dose rates conservatively overestimate the dose to individuals within a population. Following this paradigm will likely lead to misguided recommendations for risk management. The GPS-dosimetry data also demonstrated the critical importance of how modeled external dose rates are impacted by the scale at which contaminants are mapped. When contaminant mapping scales are coarse even detailed knowledge about each animal's home range was inadequate to accurately predict external dose rates. Importantly, modeled external dose rates based on a single measurement at a trap site did not correlate to actual dose rates measured on free ranging animals. These findings provide empirical data to support published concerns about inadequate dosimetry in much of the published Chernobyl and Fukushima dose-effects research. Our data indicate that a huge portion of that literature should be challenged, and that improper dosimetry remains a significant source of controversy in radiation dose-effect research.
PubMed: 38905881
DOI: 10.1016/j.jenvrad.2024.107472 -
Health Physics Jun 2024The As Low As Reasonably Achievable (ALARA) principle includes taking into account economic and societal factors. To consider these factors, decision-aiding techniques...
The As Low As Reasonably Achievable (ALARA) principle includes taking into account economic and societal factors. To consider these factors, decision-aiding techniques such as cost-benefit analysis were introduced by the International Commission on Radiological Protection (ICRP) 50 y ago. Over the years, developments in health economics have led to new ways of deriving the concept of a value of a statistical life (VSL), which now is influencing the monetary value assigned to a unit of collective dose for radiological protection purposes (the α value) used in cost-benefit analyses. The aim of the present study was to estimate an α value useful for occupational radiological protection within the healthcare system of Sweden. A survey based on the stated preference approach was developed and sent to staff who are exposed to ionizing radiation at their work in Region Västra Götaland (Sweden). The survey essentially contained two scenarios: the respondents' willingness to pay for measures against radon exposure at home and their willingness to accept compensation for x-ray exposure at work. Answers from 718 respondents were collected. In the sensitivity analysis of the survey, the overall median VSL based on the two scenarios was calculated to be $50 million (IQR $10 to 363 million). The corresponding α value was established to $1,600 person-mSv -1 ($2,100 person-mSv -1 if excess burden of taxes is excluded). The recommended α value is in the high end compared to other studies but within the interval of values being used by nuclear utilities today. The α value should be seen in the light of ICRP's recommendation about stakeholder involvement as an important part of the optimization process.
PubMed: 38905453
DOI: 10.1097/HP.0000000000001848 -
Journal of the American Heart... Jun 2024The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. We...
BACKGROUND
The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. We examined whether irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared with long-term administration.
METHODS AND RESULTS
C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy X-ray head-and-neck irradiation. Pravastatin was then administered either for an additional 24 hours or for 1 year. Carotid arteries were tested for vascular reactivity, altered gene expression, and collagen deposition 1 year after irradiation. Treatment with pravastatin for 24 hours after irradiation reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction. Expression of markers associated with inflammation (NFκB p65 [phospho-nuclear factor kappa B p65] and TNF-α [tumor necrosis factor alpha]) and with oxidative stress (NADPH oxidases 2 and 4) were lowered and subunits of the voltage and Ca activated K BK channel (potassium calcium-activated channel subfamily M alpha 1 and potassium calcium-activated channel subfamily M regulatory beta subunit 1) in the carotid artery were modulated. Treatment with pravastatin for 1 year after irradiation completely reversed irradiation-induced changes.
CONCLUSIONS
Short-term administration of pravastatin is sufficient to reduce chronic vascular injury at 1 year after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.
PubMed: 38904226
DOI: 10.1161/JAHA.123.033558 -
Frontiers in Oncology 2024The utility of pre- and post-operative alpha-fetoprotein (AFP) and des-gamma (γ)-carboxy prothrombin (DCP) expression patterns and their dynamic changes as predictors...
Prognostic implications of preoperative, postoperative, and dynamic changes of alpha-fetoprotein and des-gamma (γ)-carboxy prothrombin expression pattern for hepatocellular carcinoma after hepatic resection: a multicenter observational study.
BACKGROUND
The utility of pre- and post-operative alpha-fetoprotein (AFP) and des-gamma (γ)-carboxy prothrombin (DCP) expression patterns and their dynamic changes as predictors of the outcome of hepatic resection for hepatocellular carcinoma (HCC) has yet to be well elucidated.
METHODS
From a multicenter database, AFP and DCP data during the week prior to surgery and the first post-discharge outpatient visit (within 1-2 months after surgery) were collected from patients with HCC who underwent hepatectomy. AFP-DCP expression patterns were categorized according to the number of positive tumor markers (AFP ≥ 20ng/mL, DCP ≥ 40mAU/mL), including double-negative, single-positive, and double-positive. Changes in the AFP-DCP expression patterns were delineated based on variations in the number of positive tumor markers when comparing pre- and post-operative patterns.
RESULTS
Preoperatively, 53 patients (8.3%), 337 patients (52.8%), and 248 patients (38.9%) exhibited double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Postoperatively, 463 patients (72.6%), 130 patients (20.4%), and 45 patients (7.0%) showed double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Survival analysis showed a progressive decrease in recurrence-free (RFS) and overall survival (OS) as the number of postoperative positive tumor markers increased (both < 0.001). Multivariate analysis showed that postoperative AFP-DCP expression pattern, but not preoperative AFP-DCP expression pattern, was an independent risk factor for RFS and OS. Further analysis showed that for patients with positive preoperative markers, prognosis gradually improves as positive markers decrease postoperatively. In particular, when all postoperative markers turned negative, the prognosis was consistent with that of preoperative double-negative patients, regardless of the initial number of positive markers.
CONCLUSIONS
AFP-DCP expression patterns, particularly postoperative patterns, serve as vital sources of information for prognostic evaluation following hepatectomy for HCC. Moreover, changes in AFP-DCP expression patterns from pre- to post-operation enable dynamic prognostic risk stratification postoperatively, aiding the development of individualized follow-up strategies.
PubMed: 38903723
DOI: 10.3389/fonc.2024.1425292 -
Biochemistry and Biophysics Reports Jul 2024Single-molecule intramolecular dynamics were successfully measured for three variants of SARS-CoV-2 spike protein, alpha: B.1.1.7, delta: B.1.617, and omicron:...
Single-molecule intramolecular dynamics were successfully measured for three variants of SARS-CoV-2 spike protein, alpha: B.1.1.7, delta: B.1.617, and omicron: B.1.1.529, with a time resolution of 100 μs using X-rays. The results were then compared with respect to the magnitude and directions of motions for the three variants. The largest 3-D intramolecular movement was observed for the omicron variant irrespective of ACE2 receptor binding. A more detailed analysis of the intramolecular motions revealed that the distribution state of intramolecular motion for the three variants was completely different with and without ACE2 receptor binding. The molecular dynamics for the trimeric spike protein of the omicron variant increased when ACE2 binding occurred. At that time, the diffusion constant increased from 71.0 [mrad/ms] to 91.1 [mrad/ms].
PubMed: 38903159
DOI: 10.1016/j.bbrep.2024.101712 -
Dental Materials : Official Publication... Jun 2024Commercially available resin cements consist of various filler sizes, filler content and monomers, and it is unclear which of these factors have the greatest effect on...
STATEMENT OF PROBLEM
Commercially available resin cements consist of various filler sizes, filler content and monomers, and it is unclear which of these factors have the greatest effect on the color stability of laminate veneers.
OBJECTIVES
To evaluate the color stability of lithium disilicate-reinforced laminate veneers inserted with three commercial resin cements with various filler sizes/contents and monomers upon accelerated aging.
METHODS
Veneers were fabricated and cemented on resin abutments using three commercially available resin cements comprised of two different monomers and varying filler sizes/contents: 1) triethylene glycol dimethacrylate, TEGDMA (RelyX™ Veneer = 0.6 µm/66 %, Calibra® Esthetic Light Cure =1.2 µm/65 %); and 2) urethane dimethacrylate, UDMA (Variolink Esthetic LC = 0.1 µm/38 %). A total of 60 specimens were fabricated (n = 20 for each cement). The relative number of particles (N) and relative surface area (A) were calculated for each filler size/content. Color coordinates (L*, a*, b*) were measured, and color change (ΔE) was calculated after cementation and following aging at 150, 300, 450, and 600 h using xenon light. Differences in color coordinates and color change were determined using repeated measures ANOVA followed by Tukey's post hoc test (α = .05). A post-hoc power analysis was performed to confirm reliability of the results.
RESULTS
Based on a post-hoc power analysis of a repeated measures ANOVA with two between-factors and 1 within-factor, we had 89 % power to detect a difference of effect by cement type, 10 % power to detect a difference by shade, and 100 % power to detect a difference of effect by aging. The UDMA-based cement (0.1 µm/38 %) was least affected by aging, despite having the largest number of particles (N = 1010) and largest particle surface area (A = 7.02). The TEGDMA-based cements exhibited a significant color change, with 0.6 µm/66 % (A = 2.03, N = 8.12) producing a larger ΔE than 1.2 µm/65 % (A = 1.00, N = 1.00).
CONCLUSIONS
Among the commercial cements tested, UDMA-based resin (0.1 µm/38 %) provided better color stability than TEGDMA-based resin cements. The color change after aging was affected by the relative surface area and relative number of particles for the TEGDMA-based resin cement (0.6 µm/66 % and 1.2 µm/65 %), with a larger surface area and a higher relative number of particles, accelerated color change with aging. The present study demonstrates a novel approach to determine color stability for any resin cement with particulate filler.
CLINICAL IMPLICATIONS
The dental practitioner should be selective in choosing a commercial light cure cementation product for laminate veneers, as UDMA containing resin cement is more resistant to color changes over time than TEGDMA, regardless of the filler size/content.
PubMed: 38902146
DOI: 10.1016/j.dental.2024.06.001 -
Environmental Research Jun 2024The fruit Pyrus communis, owing to its presence of phenolics and flavonoids, was chosen for its nanoparticle's reducing and stabilizing properties. Furthermore, the zinc...
The fruit Pyrus communis, owing to its presence of phenolics and flavonoids, was chosen for its nanoparticle's reducing and stabilizing properties. Furthermore, the zinc metal may be nano-absorbed by the human body. As a result, the study involves synthesizing zinc oxide nanoparticles (ZnO NPs) from P. communis fruit extract using the green method. The synthesized nanoparticle was examined with a UV-visible spectrophotometer, Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and Dynamic Light Scattering (DLS). When absorption studies were performed with a UV-visible spectrophotometer, the nanoparticle exhibited a blue shift. The FTIR spectrum revealed the molecular groups present in both the fruit extract and metal. In the SEM analysis, the ZnO NPs appeared as spherical particles, agglomerated together, and of nano-size. The larger size of the ZnO NPs in DLS can be attributed to their ability to absorb water. After characterization, nanoparticles were tested for anti-diabetic (α-amylase and yeast glucose uptake activity) and anti-microbial properties. The α-amylase inhibition percentage was 46.46 ± 0.15% for 100 μg/mL, which was comparable to the acarbose inhibition percentage of 50.58 ± 0.67% at the same concentration. The yeast glucose uptake activity was 64.24 ± 0.80% at 20 mM glucose concentration, which was comparable to the standard of 78.03 ± 0.80. The nanoparticle was more effective against Gram-negative bacteria Shigella sp. and Salmonella typhi than against Gram-positive bacteria Bacillus cereus and Streptococcus pneumoniae.
PubMed: 38901812
DOI: 10.1016/j.envres.2024.119450 -
Free Radical Biology & Medicine Jun 2024Repeated sevoflurane exposure in neonatal mice triggers neuroinflammation with detrimental effects on cognitive function. Yet, the mechanism of the sevoflurane-induced...
Repeated sevoflurane exposure in neonatal mice triggers neuroinflammation with detrimental effects on cognitive function. Yet, the mechanism of the sevoflurane-induced cytokine response is largely unknown. In this study, we reveal that 3-MA, an autophagy inhibitor, attenuated the sevoflurane-induced neuroinflammation and cognitive dysfunction, including the decreased freezing time and fewer platform crossings, in the neonate mice. 3-Methyladenine (3-MA) suppressed sevoflurane-induced expression of interleukin-6 and tumor necrosis factor-alpha in vitro. Moreover, sevoflurane activates IRF3, facilitating cytokine transcription in an AKT3-dependent manner. Mechanistically, sevoflurane-induced autophagic degradation of dehydrocholesterol-reductase-7 (DHCR7) resulted in accumulations of its substrate 7-dehydrocholesterol (7-DHC), mimicking the effect of sevoflurane on AKT3 activation and IRF3-driven cytokine expression. 3-MA significantly reversed sevoflurane-induced DHCR7 degradation, AKT phosphorylation, IRF3 activation, and the accumulation of 7-DHC in the hippocampal CA1 region. These findings pave the way for additional investigations aimed at developing novel strategies to mitigate postoperative cognitive impairment in pediatric patients.
PubMed: 38901498
DOI: 10.1016/j.freeradbiomed.2024.06.012