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  • 2024

    AbstractBackgroundEndoplasmic reticulum (ER) stress signaling pathways have pivotal roles in atherosclerosis progression. Recently, we have developed Kyoto University Substance (KUS) 121, which selectively inhibits ATPase activities of valosin-containing protein (VCP) and consequently saves intracellular ATP consumption and mitigates ER stress.Methods and ResultsWe assessed the efficacy of KUS121 against atherosclerosis by its daily injection intoApoe−/−mice fed with Western Diet (WD) for 8 weeks. Consequently, KUS121 treatment reduced atherosclerosis progression by approximately 40% in atherosclerotic plaques. Interestingly, we found that C/EBP homologous protein (CHOP), an established ER stress marker, was mainly expressed in plaque endothelium. Therefore, we assessed the action of KUS121 in endothelial cells using the human endothelial cell line (EA.hy926 cells). As a result, KUS121 prevented ER stress-induced apoptosis and downregulated the IRE1 (Inositol-requiring enzyme) α-associated inflammatory pathways. Consistent with these in vitro findings, KUS121 treatment also significantly reduced endothelial apoptosis assessed by TUNEL staining and inflammation examined by immunostaining of Nuclear factor kappa B (NF-κB) and Intercellular adhesion molecule (ICAM) 1 at plaque endothelium. We also demonstrated that KUS121 maintained ATP levels in EA.hy926 cells and atherosclerotic plaque lesions using the single-wavelength or the FRET-based fluorescent ATP sensor. Supplementation of intracellular ATP by Methyl pyruvate (MePyr) attenuated ER stress-induced apoptotic and inflammatory pathways in endothelial cells, which could be the main mechanism how KUS121 reduces ER stress.ConclusionsKUS121 can be a new therapeutic option for atherosclerotic diseases by maintaining intracellular ATP levels and attenuating ER stress-induced apoptosis and inflammation in plaque endothelium.
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  • 2024

    AbstractThe cell nucleus is a dynamic structure repeating disassembly and reformation during mitosis. Reformation of the nucleus is essential for cell proliferation, and therefore, the factors required for nuclear reformation are fundamental for eukaryotes. Although various factors have been identified inin vitrosystems using frog egg extracts andin vivoimaging of somatic cells, little is known about the factors required for the formation of functional nuclear structures in living mouse eggs. To identify such factors, we used a reconstruction approach to construct an artificial nucleus around DNA in mouse eggs. T4 phage DNA (166 kbp) was microinjected into living mouse oocytes. Amounts of DNA injected and injection timing were examined to determine the conditions appropriate for the formation of functional nuclei. Microinjection of 100-500 ng/µl DNA during metaphase through telophase of the second meiosis, but not the subsequent interphase, was important for the formation of artificial nucleus. This T4 DNA-derived artificial nucleus had the structure of nuclear lamina and nuclear pore complexes, and nuclear transport activity, similar to natural nuclei. These results suggest that exogenous DNA can form a functional nucleus in mouse oocytes, regardless of the sequence or the source of DNA.
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  • 2024

    AbstractPurposeWe present an observational study involving free-breathing short-scan-time dynamic MRI (dMRI) method that can be routinely used for computing dynamic lung volumes accurately.Materials and Methods(i) Full-resolution free-breathing sagittally-acquired 2D dMRI scans are gathered from 45 normal children via True-FISP sequence. Sparse dMRI (s-dMRI) scans are simulated from these datasets by subsampling in the spatio-temporal domains via a limited numberNSSof selected sagittal locations andTSSof time instances (respectively,NFSandTFSfor full scan). (ii) A 4D image is constructed from both full and sparse scans. Lungs are segmented from 4D image, and their volumes from full (VF) and sparse dMRI (VS) scans are computed. (iii) A regression model is fit forVFas a function ofVSon a training set, and the full-resolution volumeVPpredicted by the model is estimated fromVS. (iv) The deviation ofVPfromVFis analyzed on both synthesized sparse dMRI scans from a separate full-resolution test set and actual s-dMRI scans prospectively acquired from 10 normal children.ResultsWithNSS=5 (per lung) andTSS=40, the deviation ofVPfromVFwas ∼2% with a total scan-time of ∼9 min (45-60 min for the full scan withNFS=15-22 (per lung) andTFS=80). These metrics become 0.4%, and <20 min for s-dMRI withNSS=15-22 (per lung) andTSS=40.Conclusions-dMRI is a practical approach for computing dynamic lung volumes that can be used routinely with no radiation concern, especially on patients who cannot tolerate long scan times.
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  • 2024

    Nuclear speckles, a type of membraneless nuclear organelle in higher eukaryotic cells, play a vital role in gene expression regulation. Using the reverse transcription-based RNA-binding protein binding sites sequencing (ARTR-seq) method, we study human transcripts associated with nuclear speckles. We identify three gene groups whose transcripts demonstrate different speckle localization properties and dynamics: stably enriched in nuclear speckles, transiently enriched in speckles at the pre-mRNA stage, and not enriched in speckles. Specifically, we find that stably-enriched transcripts contain inefficiently spliced introns. We show that nuclear speckles specifically facilitate splicing of speckle-enriched transcripts. We further reveal RNA sequence features contributing to transcript speckle localization, underscoring a tight interplay between genome organization, RNA cis-elements, and transcript speckle enrichment, and connecting transcript speckle localization with splicing efficiency. Finally, we show that speckles can act as hubs for the regulated retention of introns during cellular stress. Collectively, our data highlight a role of nuclear speckles in both co- and post-transcriptional splicing regulation.
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  • 2024


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  • 2024

    A laser is amplified light beam to emit radiation. these rays are used in surgery by accurately projecting laser light to remove diseased tissue or bleed blood vessels by heating the target cells until they explode. The laser is used medically under objective or complete anesthesia. There are many types of lasers such as carbon dioxide laser, YAG laser, and argon beam, and each type of laser has a specific use, and each type of surgery and tissue has a special color of laser light. the uses of the laser in the surgery are multiple. brain and liver tumors can be removed while not to damage the healthy tissue surrounding the tumors. Lymphatic vessels can be closed to reduce the spread of tumor cells and nerve endings to reduce pain after surgery, small bleeding blood vessels can be closed, in addition to removing warts and skin tumors. A general advantage of laser surgery is the absence of bleeding, reduced surgical infections, pain and wound size, and a short hospital stay. The recovery period after laser treatment depends on the type of pathological condition and the patient's health condition before treatment. In the end: the laser has successful surgical uses to obtain good results with minimal complications, and contrary to what is common, its medical uses are specific to certain diseases and not for all types of surgery. In addition, laser treatment requires modern and complex devices and experienced experts in their use
    • Book : 1(4)
    • Pub. Date : 2024
    • Page : pp.12-18
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  • 2024

    ABSTRACTPeroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates gene expression programs in response to ligand binding. Endogenous lipids and synthetic ligands, including covalent antagonist inhibitors such as GW9662 and T0070907, are thought to compete for the orthosteric pocket in the ligand-binding domain (LBD). However, we previously showed that synthetic PPARγ ligands can cooperatively cobind with and reposition a bound endogenous orthosteric ligand to an alternate site, synergistically regulating PPARγ structure and function (Shang et al., 2018). Here, we reveal the structural mechanism of cobinding between a synthetic covalent antagonist inhibitor with other synthetic ligands. Biochemical and NMR data show that covalent antagonist inhibitors weaken—but do not prevent—the binding of other synthetic ligands via an allosteric mechanism rather than direct ligand clashing. The covalent ligands shift the LBD ensemble toward a transcriptionally repressive conformation, which structurally clashes with and reduces the orthosteric binding affinity of non-covalent synthetic ligands. Crystal structures reveal different non-covalent synthetic ligand-specific cobinding mechanisms ranging from alternate site binding to unexpectedly adopting an orthosteric binding mode by altering the covalent ligand binding pose. Our findings not only highlight the significant flexibility of the PPARγ orthosteric pocket and its ability to accommodate multiple ligands simultaneously, but also demonstrate that GW9662 and T0070907 should not be used as reliable chemical tools to inhibit the binding of other ligands to PPARγ.
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  • 2024

    Abstract

    Background The NONO gene is located on chromosome Xq13.1 and encodes a nuclear protein involved in RNA synthesis, transcriptional regulation, and DNA repair. Hemizygous loss-of-function variants in NONO reportedly cause X-linked syndromic intellectual developmental disorder-34 (MRXS34) in males. At present, there are few clinical reports related to MRXS34, and the mutation spectrum of NONO-related diseases has not been completely determined. Methods We report the case of a fetus with noncompaction cardiomyopathy, a short anteroposterior diameter of the corpus callosum and relative macrocephaly. Genotyping examination, including chromosome microarray analysis (CMA) and trio-medical exon sequencing, was performed. Results Medical exon sequencing revealed a de novo hemizygous nonsense mutation (c.214 C > T, p.Gln72Ter) in exon 4 of the NONO gene. A review of previous literature suggested that noncompaction cardiomyopathy, abnormalities of the corpus callosum, and macrocephaly are consistent phenotypes of MRXS34. Conclusion The mutation (c.214 C > T, p.Gln72Ter) in the NONO gene was present in a fetus with MRXS34. This study expands the mutation spectrum of NONO-related diseases and enlarges noncompaction cardiomyopathy, abnormalities of the corpus callosum and macrocephaly to the phenotype of MRXS34 in fetuses.


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    • Pub. Date : 2024
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  • 2024

    The study conducts a comparative analysis of solar radiation estimation methods, assessing the efficacy of the Heliosat-2 algorithm against ground measurements across seven distinct countries: Netherlands, Spain, Japan, Namibia, South Africa, Saudi Arabia, and India. To achieve this, it utilizes two distinct satellite data sources—Himawari-8 for Japan and Metosat Second Generation-MSG for the rest of the countries—spanning the years Jan 2022 to April 2024. A robust methodology for determining albedo parameters specific to Heliosat-2 was developed. During cloudy days, the estimates provided by Heliosat-2 generally exceeded the ground measurements in all the countries. Conversely, on clear days, there was a tendency for underestimation, as indicated by the median value of the mean bias (MB) across most of the countries. The Heliosat-2 model slightly underestimates daily radiation values, with a median MB ranging from −27.5 to +10.2 W.m⁻². Notably, the median root mean squared error (RMSE) on clear days is significantly lower, with values ranging from 24.8 to 108.7 W.m⁻², compared to cloudy days where RMSE values lie between 75.3 and 180.2 W.m⁻². In terms of R² values, both satellites show a strong correlation between the estimated and actual values, with a median value consistently above 0.86 on a monthly scale and over 92% of daily data points falling within ±2 standard deviation.
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  • 2024

    . The present work is devoted to the study of nitric oxide production in yeast cells after exposure to UV-B radiation. In addition, a comparative evaluation of the production of reactive oxygen species (ROS) was carried out. The change in the level of ROS was determined using the fluorescent dye 2',7'-dichlorodihydrofluorescein diacetate-H2DCF•DA. That dye is used to determine the level of ROS in living cells. We determined the intracellular concentration of nitric oxide using a fluorescent dye; -4-amino-5-methylamino-2',7'-difluorescein diacetate (DAF-FM). It was found that under the action of UV-B radiation on cells, depending on the dose, the rate of oxidation of the dye 2',7'-dichlorodihydrofluorescein diacetate (H2DCF•DA) increases and a high intensity of DCF fluorescence is observed. Under the action of a high dose (4,8∙102 erg/mm2.) of UV-B rays, the generation of ROS and nitric oxide decreases. As can be seen on the obtained data, at high doses of radiation, the intensity of chemiluminescence of lucigenin remains at a high level.
    • Book : 8(1)
    • Pub. Date : 2024
    • Page : pp.12-15
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