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The ionosphere can be artificially modified by employing ground-based high-power high-frequency electromagnetic waves to irradiate the ionosphere. This modification is achieved through the nonlinear interaction between the electromagnetic waves and the ionospheric plasma, leading to changes in the physical properties and structure of the ionosphere. The degree of artificial modification of the ionosphere is closely related to the heating energy density of high-frequency pump waves. Due to the high density of neutral constituents in the lower ionosphere and the high frequency of electron-neutral collisions, the energy of heating pump waves will be absorbed and attenuated during the penetration of the low ionosphere, seriously affecting the heating effect. This paper proposes a method to reduce the absorption of ionospheric heating pump waves by releasing electron attachment chemicals into low ionosphere to form a large-scale electron density hole. A model for mitigating pump waves absorption based on SF6 release is established, and the absorption at different frequencies is quantitatively calculated. The propagation characteristics of high-frequency signals in ionospheric holes are studied using a three-dimensional ray tracing method, and the results demonstrate that the chemical release method not only reduces the absorption attenuation of heating pump waves but also forms spherical electron density holes, which exhibit a focusing effect on the heating beam and enhance the heating effect. The results are of great significance for understanding the nonlinear interaction between electromagnetic wave and ionospheric plasma and improving the ionospheric heating efficiency.

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Sarcoplasmic calcium-binding protein (Cra a 4) from Crassostrea angulata belongs to the EF-hand superfamily, and understanding of its structure-allergenicity relationship is still insufficient. In this study, chemical denaturants were used to destroy the structure of Cra a 4, showing that disruption of the structure reduced its IgG-/IgE-binding activity. To explore which critical amino acid site affects the allergenicity of Cra a 4, the mutants were obtained by site-directed mutations in the disulfide bonds site (C97), conformational epitopes (I105, D114), or Ca2+-binding region (D106, D110) and their IgG-/IgE-binding activity was reduced significantly using serological tests. Notably, C97A had the lowest immunoreactivity. In addition, two conformational epitopes of Cra 4 were verified. Meanwhile, the increase of the α-helical content, surface hydrophobicity, and surface electrostatic potential of C97A affected its allergenicity. Overall, the understanding of the structure-allergenicity relationship of Cra a 4 allowed the development of a hypoallergenic mutant.

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BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital heart disease. However, the prevalence, clinical characteristics, and current management of BAV associated with inherited cardiomyopathy, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular noncompaction (LVNC) have not been well described. METHODS: Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM, DCM, and LVNC based on clinical and echocardiographic criteria. Patients with coexistent conditions were investigated further. RESULTS: Of 3533 patients with BAV screened, 57 (1.6%) had concomitant cardiomyopathy. BAV was combined with HCM in 30 of these patients, with DCM in 19, and with LVNC in eight. Forty-six patients (80.7%) were male, and the mean age at first diagnosis was 47 years for BAV with HCM, 49 years for BAV with DCM, and 35 years for BAV with LVNC. Heart failure and aortic valve dysfunction were common in these patients, and the prevalence of coexisting aortopathy was 43.3%, 26.3% and 25.0%, respectively, for BAV with HCM, DCM and LVNC. During the index hospitalization, 24 of the 57 patients (42.1%) underwent surgery, 16 (28%) underwent aortic valve and/or aortic surgery, and 16 of the 30 patients with HCM had a Morrow procedure. There were no deaths or other major adverse cardiovascular events. CONCLUSIONS: The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general population. Aortopathy and heart failure were common, with almost half of patients requiring surgery at diagnosis.

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Marine bivalves are rich in docosahexaenoic acid (DHA), a polyunsaturated fatty acid known to be beneficial for human health; however, the potential role of DHA in protecting shellfish from the toxicity of diarrhetic shellfish toxins (DSTs) remains poorly understood. Here, we aimed to study the effect of DHA on the response of the bivalve, Perna viridis, to DSTs by using LC-MS/MS, RT-qPCR, and histological examination. In this study, we observed that the DHA content decreased significantly with esterification of DSTs in the digestive gland of the mussel P. viridis after 96 h of exposure to Prorocentrum lima, a DST-producing dinoflagellate. The addition of DHA significantly increased the esterification level of DSTs and increased the expression of Nrf2 signaling pathway-related genes and enzyme activities, alleviating the damage of DSTs to digestive glands. These results suggested that DHA may mediate the esterification of DSTs and activation of the Nrf2 signaling pathway in P. viridis to protect mussels from the toxic effects of DSTs. This study may provide new insights regarding the response of bivalves to DSTs and lay the foundation for uncovering the role of DHA in environmental adaptation of bivalves.

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Commercial nano-scale carbon blacks (CB) are being harnessed widely and may impose potentially hazardous effects because of their unique properties, especially if they have been modified to grow reactive functional groups on their surface. Cytotoxicity of CB has been well studied but the membrane damage mechanisms and role of surface modification are still open to debate. Negatively and positively charged giant unilamellar vesicles (GUVs) were prepared using three lipids as model cell membranes to examine the mechanistic damage of CB and MCB (modified by acidic potassium permanganate) aggregates. Optical images showed that both anionic CB and MCB disrupted the positively charged but not the negatively charged GUVs. This disruption deteriorated with the rise and extension of exposure concentration and time. Lipids extraction caused by CBNs (CB and MCB together are called CBNs) was found. MCB caused more severe disruption than CB. MCB was enveloped into vesicles through an endocytosis-like process at 120 mg/L. MCB mediated the gelation of GUVs, perhaps through C-O-P bonding bridges. The lower hydrodynamic diameter and more negative charges may have been responsible for the distinction effect of MCB over CB. The adhesion and bonding of CBNs to the membrane were favored by electrostatic interaction and the practical application of CBNs warrants more attention.

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BACKGROUND: Left ventricular noncompaction (LVNC) is an increasingly recognised cardiomyopathy of which a significant percentage are genetic in origin. The purpose of the present study was to identify potential pathogenic mutation leading to disease in a Chinese LVNC family. METHODS: A 3-generation family affected by LVNC was recruited. Clinical assessments were performed on available family members, with clinical examination, ECG, echocardiography and cardiac MRI. The proband (I-2), the proband's daughter (II-1, affected) and mother (III-1, unaffected) were selected for WGS. Sanger sequencing were performed in all of the 4 surviving family members. RESULTS: Combined whole genome sequencing with linkage analysis identified a novel missense mutation in the giant protein obscurin (OBSCN NM_001098623, c.C19063T), as the only plausible disease-causing variant that segregates with disease among the four surviving individuals, with interrogation of the entire genome excluding other potential causes. This c.C19063T missense mutation resulted in p.R6355W in the encoded OBSCN protein. It affected a highly conserved residue in the C terminus of the obscurin-B-like isoform between the PH and STKc domains, which was predicted to affect the function of the protein by different bioinformatics tools. CONCLUSIONS: Here we present clinical and genetic evidence implicating the novel R6355W missense mutation in obscurin as the cause of familial LVNC. This expands the spectrum of obscurin's roles in cardiomyopathies. It furthermore highlights that rare obscurin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. This study also provided new insights into the molecular basis of OBSCN mutation positive LVNC.

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[This corrects the article DOI: 10.3389/fped.2022.887214.].

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Background: Liddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, ß, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family. Methods: DNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism. Results: We identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome. Conclusion: c.1691_1693delinsG, a novel frame-shift mutation in the ß subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.

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Objective: Liddle syndrome (LS) is a monogenic hypertension consistent with autosomal dominant inheritance, often with early onset high blood pressure in childhood or adolescence. This study aimed to identify the pathogenicity of a nonsense mutation in SCNN1G in a Chinese family with LS and the long-term outcomes of tailored treatment with amiloride. Methods: To explore the pathogenicity of candidate variant reported in 2015 by our team, we constructed mutant and wild-type models in vitro and measured amiloride-sensitive current in Chinese Hamster Ovary (CHO) cells using patch clamp technique. Participants were followed up for 7 years after tailored treatment with amiloride. Results: A nonsense variant was detected in six members, two of whom were pediatric patients. This mutation resulted in a termination codon at codon 572, truncating the Pro-Pro-Pro-X-Tyr motif. The mutant epithelial sodium channels displayed higher amiloride-sensitive currents than the wild-type channels (P < 0.05). Tailored treatment with amiloride achieved ideal blood pressure control in all patients with normal cardiorenal function, and no adverse events occurred during follow-up. Conclusion: We found the pathogenicity of a nonsense SCNN1G mutation (p.Glu571*) with enhanced amiloride-sensitive currents in a LS family with young patients. Tailored treatment with amiloride may be an effective strategy for the long-term control of blood pressure and protection from target organ damage or cardiovascular events, including children and youth patients with LS.

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BACKGROUND: Mutation in the titin gene (TTN) in left ventricular noncompaction (LVNC) has been reported with a highly heterogeneous prevalence, and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacterized. In the present study, we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies. METHODS: The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autosomal dominant LVNC cardiomyopathy. The clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro, in which functional studies were carried out and characterized in comparison to its wild-type counterpart. RESULTS: A novel truncating mutation TTN p. R2021X was identified as the only plausible disease-causing variant that segregated with disease among the five surviving affected individuals, with an interrogation of the entire genome excluding other potential causes. Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haploinsufficient disease mechanism in titin truncation mutation cardiomyocytes. Further functional studies suggested mitochondrial abnormities in the presence of mutation, including decreased oxygen consumption rate, reduced adenosine triphosphate production, impaired activity of electron translation chain, and abnormal mitochondrial structure on electron microscopy. Impaired autophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p. R2021X truncation mutation cardiomyocytes. CONCLUSIONS: The TTN p. R2021X mutation has a function in the cause of a highly penetrant familial LVNC. These findings expand the spectrum of titin's roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.

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The purpose of this study was to investigate the effect of Huaier extract supernatant(HES) on the proliferation, apoptosis, autophagy, and migration of human gastric cancer HGC-27 and MGC-803 cells and its molecular mechanisms. The main components in HES were preliminarily analyzed by high-performance liquid chromatography-mass spectrometry(HPLC-MS). Methyl thiazolyl tetrazolium(MTT) assay, colony formation assay, and 5-ethynyl-2'-deoxyuridine(EdU) staining assay were used to explore the effect of HES on the proliferation of human gastric cancer HGC-27 and MGC-803 cells. Hoechst staining and flow cytometry assay were used to determine the effect of HES on apoptosis of human gastric cancer HGC-27 and MGC-803 cells. Acridine orange staining and cell scratch assay were used to determine the effect of HES on autophagy and migration of human gastric cancer HGC-27 and MGC-803 cells, respectively. Western blot was used to investigate the regulatory effect of HES on the expression levels of proteins related to apoptosis, epithelial-mesenchymal transition(EMT), and signaling pathways in human gastric cancer HGC-27 and MGC-803 cells. The results showed that HES mainly contained some components with high polarities. HES significantly reduced the cell viability of human gastric cancer cells in a dose-and time-dependent manner. The IC_(50 )values after 48 h of HES treatment in human gastric cancer HGC-27 and MGC-803 cells were 7.56 and 10.77 g·L~(-1), respectively. Meanwhile, HES inhibited the colony-forming ability and short-term proliferation of human gastric cancer cells. The apoptosis rates of HGC-27 and MGC-803 cells treated with 8 g·L~(-1) HES for 72 h were 62.13%±8.92% and 54.50%±3.26%, respectively. HES also promoted autophagy in human gastric cancer cells and impaired their migration ability in vitro. Moreover, HES up-regulated the cleavage of the apoptosis marker poly ADP-ribose polymerase(PARP) and the protein expression level of the epithelial cell marker E-cadherin, and down-regulated the protein levels of phosphorylated-mammalian target of rapamycin(p-mTOR), phosphorylated-S6(p-S6), and phosphorylated-extracellular signal-regulated kinase(p-ERK) in human gastric cancer cells. Therefore, HES is one of the effective anti-tumor components of Huaier, which inhibits the proliferation and migration of human gastric cancer cells, and induces apoptosis and autophagy. Moreover, the mTOR signal and ERK signal may be involved in the anti-gastric cancer effect of HES. This study provides novel references for the in-depth research and clinical application of Huaier. It is also of great significance to promote the scientific development and utilization of Huaier.

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Circadian clock is an internal autonomous time-keeping system, including central clocks located in the suprachiasmatic nucleus (SCN) and peripheral clocks. The molecular circadian clock consists of a set of interlocking transcriptional-translational feedback loops that take the clock-controlled genes 24 h to oscillate. The core mechanism of molecular circadian clock is that CLOCK/BMAL1 dimer activates the transcription of cryptochromes (CRYs) and Periods (PERs), which act as transcriptional repressors of further CLOCK/BMAL1-mediated transcription. In addition to this basic clock, there is an additional sub-loop of REV-ERBα and RORα regulating the transcription of BMAL1. Approximately 80% protein-coding genes demonstrate significant rhythmicity. The earth rotation is responsible for the generation of the daily circadian rhythms. To coordinate metabolic balance and energy availability, almost all organisms adapt to the rhythm. Studies have shown that circadian clock integrating with metabolic homeostasis increases the efficiency of energy usage and coordinates with different organs in order to adapt to internal physiology and external environment soon. As the central organ of metabolism, the liver performs various physiological activities nearly all controlled by the circadian clock. There are multiple interactive regulation mechanisms between the circadian clock and the regulation of liver metabolism. The misalignment of metabolism with tissue circadian is identified as a high-risk factor of metabolic diseases. This article reviews the recent studies on circadian physiological regulation of liver glucose, lipid and protein metabolism and emphasizes oscillation of mitochondrial function. We also take an outlook for new methods and application of circadian clock research in the future.

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BACKGROUND: The prevalence of Fabry disease (FD) in Chinese patients with hypertrophic cardiomyopathy (HCM) is unclear. We aimed to evaluate the prevalence, clinical characteristics, and outcomes of FD in Chinese patients with HCM. METHODS: Of 217 patients with HCM, FD probands were screened by next-generation sequencing at Fuwai Hospital. Medical data from α-galactosidase A activity, electrocardiography, echocardiography, coronary angiography, cardiac magnetic resonance, pathological examination, and follow up was analyzed. RESULTS: Two FD probands were observed (0.93% of patients with HCM), both of which were diagnosed with symptomatic obstructive HCM at 49 years of age. One proband had a GLA mutation (c.887T>C [p.M296T]) with a late-onset cardiac variant, which was characterized by dual ventricular hypertrophy and conduction disease with a permanent pacemaker. The other patient had a GLA mutation (c.758T>C [p.I253T]) with a classic phenotype and dual ventricular hypertrophy, atrioventricular block, renal failure, and recurrent cerebral infarction. Both probands had late gadolinium enhancement mainly in the basal segment of the inferolateral wall. Follow up revealed no exertional symptoms or outflow obstruction after surgical septal myectomy in the two probands, and stable renal function was observed after 6 months of migalastat therapy in the later one. A family study revealed six female carriers and three sudden cardiac deaths. CONCLUSIONS: FD is not uncommon in Chinese patients with HCM. Multiple organic involvement, dual ventricular hypertrophy, and conduction disease provide clinical clues for suspected FD, and early genetic screening is necessary. Surgical septal myectomy and migalastat improve the long-term prognosis of patients with FD.

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As a traditional Chinese medicine, Chinese dragon's blood has multiple effects, such as activating blood to remove blood stasis, softening and dispelling stagnation, astringent and hemostasis, clearing swelling and relieving pain, regulating menstruation and rectifying the blood, so it is called "an effective medicine of promoting blood circulation". It has been widely used clinically to treat a variety of diseases. With the further research on Chinese dragon's blood, its anti-tumor medicinal value is gradually emerging. Modern pharmacological studies have shown that Chinese dragon's blood exerts anti-tumor effects mainly by inhibiting cell proliferation, inducing apoptosis, inducing DNA damage and cell cycle arrest, inducing senescence and autophagy of tumor cells, inhibiting metastasis and angiogenesis, as well as reversing multidrug resistance. This article focuses on the research progress on anti-tumor effects of Chinese dragon's blood extract and its chemical components, with a view to provide new references for the in-depth research and reasonable utilization of Chinese dragon's blood.

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OBJECTIVE: To analyze the causes of renal artery stenosis (RAS) and compare the clinical characteristics in accordance with the primary disease among patients aged from 30 to 50. METHODS: Patients were grouped by etiologies of RAS. Groups were retrospectively examined and compared regarding demographic data, clinical manifestations, laboratory findings, and imaging findings. RESULTS: A total of 152 patients (74 females, 78 males; mean age: 40.70 ± 6.01 years) were enrolled, including 84 patients (55.3%) with atherosclerosis (AS), 46 patients (30.3%) with Takayasu arteritis (TA), 18 patients (11.8%) with fibromuscular dysplasia (FMD), and four patients (2.6%) with other etiologies. Patients in AS group had greater body mass index, higher prevalence of comorbidities and higher rate of smoking and drinking history. TA patients showed more constitutional symptoms and vascular findings, and higher erythrocyte sedimentation rate. RAS in both AS group and TA group mainly located on ostia and proximal segments, but RAS in FMD group mainly involved middle to distal segment of renal artery. The AS group had significantly lesser stenosis than the other groups. Although renal function evaluated by the estimated glomerular filtration rate did not significantly differ among the groups, the incidence of kidney shrinkage was significantly higher in the TA and FMD groups (39.1% and 50%, respectively) than in the AS group (8.3%). The FMD group had milder cardiac damage than other groups. CONCLUSIONS: AS was the most common cause of RAS in patients aged from 30 to 50, followed by TA and FMD. The etiology of RAS should be carefully distinguished based on clinical manifestations, laboratory findings, and imaging to ensure that proper treatment is provided.

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This study aims to investigate the effect of Huaier aqueous extract on the growth and metastasis of human non-small cell lung cancer NCI-H1299 cells and its underlying mechanisms. MTT assay was used to detect the effect of Huaier aqueous extract on the proliferation of NCI-H1299 cells. Flow cytometry was used to examine the effect of Huaier aqueous extract on the apoptosis, cell cycle, and ROS level of NCI-H1299 cells. Wound healing assay was used to evaluate the effect of Huaier aqueous extract on the migration ability of NCI-H1299 cells. Western blot was used to detect the levels of proteins involving apoptosis, epithelial-mesenchymal transition(EMT), and MAPK signaling pathway in NCI-H1299 cells exposed to Huaier aqueous extract. The results showed that Huaier aqueous extract inhibited the proliferation of NCI-H1299 cells, and induced cell-cycle arrest at the phase S. Huaier aqueous extract promoted the apoptosis of NCI-H1299 cells by down-regulating the expression of anti-apoptotic protein Bcl-2. Moreover, Huaier aqueous extract increased ROS level and induced ferroptosis in NCI-H1299 cells. EMT played a critical role in cancer metastasis. Huaier aqueous extract reduced the migration ability of NCI-H1299 cells by inhibiting EMT of NCI-H1299 cells. In addition, this study revealed that Huaier aqueous extract inhibited MAPK signaling pathway in human non-small cell lung cancer NCI-H1299 cells, which may be one of Huaier's mechanisms in inhibiting growth and metastasis of NCI-H1299 cells. This study provides a new theoretical basis for the clinical treatment of lung cancer with Huaier, and important reference significance for further studies on the anti-tumor mechanisms of Huaier.

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PURPOSE: Apparent mineralocorticoid excess (AME) is an ultrarare autosomal recessive disorder resulting from deficiency of 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) caused by mutations in HSD11B2. The purpose of this study was to identify novel compound heterozygous HSD11B2 mutations in a Chinese pedigree with AME and conduct a systematic review evaluating the AME clinical features associated with HSD11B2 mutations. METHODS: Next-generation sequencing was performed in the proband, and Sanger sequencing was used to identify candidate variants in family members, 100 hypertensives, and 100 healthy controls. A predicted structure of 11ßHSD2 was constructed by in silico modeling. A systematic review was used to identify cases of HSD11B2-related AME. Data for genotyping and clinical characterizations and complications were extracted. RESULTS: Next-generation sequencing showed novel compound heterozygous mutations (c.343_348del and c.1099_1101del) in the proband with early-onset hypertension and hypokalemia. Sanger sequencing verified the monoallelic form of the same mutations in five other relatives but not in 100 hypertensives or 100 healthy subjects. In silico structural modeling showed that compound mutations may simultaneously perturb the substrate and coenzyme binding pocket. A systematic review of 101 AME patients with 54 HSD11B2 mutations revealed early-onset hypertension, hypokalemia and homozygous mutations as common features. The homozygous HSD11B2 mutations correlated with low birth weight (r = 0.285, P = 0.02). CONCLUSIONS: We report novel compound heterozygous HSD11B2 mutations in a Chinese teenager with early-onset hypertension, and enriched genotypic and phenotypic spectrums in AME. Genetic testing helps early diagnosis and treatment for AME patients, which may avoid target organ damage.

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Little is known about the potential threats of functionalized nano-carbon black (FNCB) combined with cadmium (Cd) to soil invertebrates. In this study, immunocompetent coelomocytes from Eisenia fetida are harnessed, and the joint cytotoxicity types of FNCB and Cd co-exposure are analyzed. The extracellular interaction mechanisms of FNCB and Cd were completely explored using adsorption kinetics and thermodynamics accompanied by isotherm batch experiments and Fourier infrared spectroscopy. The results indicated that functional amorphous carbon nanoparticles up to certain dose may injure cells due to their surface oxygen-containing groups. The MIXTOX model and the combination index suggested that the combined action of FNCB and Cd exhibited antagonism at the low dose/effect-level and synergism at the high dose/effect-level. FNCB decreased the intracellular free Cd2+ content at a low mixture dose, while it increased it at a high mixture dose. The adsorption of Cd on FNCB followed pseudo-second-kinetics and the Langmuir isotherm, hence better indicating a chemisorption, which was also supported by the activation energy (Ea = 36.6 kJ/mol), enthalpy change (ΔH = -98.4 kJ/mol), and functional group changes. Coordination binding should be responsible for the subsequent interaction of toxicity.

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INTRODUCTION: Liddle syndrome (LS), an autosomal dominant and inherited monogenic hypertension syndrome caused by pathogenic mutations in the epithelial sodium channel (ENaC) genes SCNN1A, SCNN1B, and SCNN1G. OBJECTIVE: This study was designed to identify a novel SCNN1B missense mutation in a Chinese family with a history of stroke, and to confirm that the identified mutation is responsible for LS in this family. METHODS: DNA samples were collected from the proband and 11 additional relatives. Next-generation sequencing was performed in the proband to find candidate variants. In order to exclude genetic polymorphism, the candidate variantin SCNN1B was verified in other family members, 100 hypertensives, and 100 healthy controls by Sanger sequencing. RESULTS: Genetic testing revealeda novel and rare heterozygous variant in SCNN1B in the proband. This variant resulted in a substitution of threonine instead of proline at codon 617, altering the PY motif of ß-ENaC. The identified mutation was only verified in 5 relatives. In silico analyses indicated that this variant was highly pathogenic. In this family, phenotypic heterogeneity was present among 6 LS patients. Tailored medicine with amiloride was effective in controlling hypertension and improving the serum potassium concentration in patients with LS. CONCLUSIONS: We identified a novel SCNN1B mutation (c.1849C>A) in a family affected by LS. Patients with LS, especially those with severe hypertension, should be alert for the occurrence of premature stroke. Timely diagnosis using genetic testing and tailored treatment with amiloride can help LS patients to avoid severe complications.

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Although glucagon-like peptide-1 (GLP-1) analogue has been reported to suppress oxidative stress in non-alcoholic fatty liver disease (NAFLD), an effective therapeutic agent for NAFLD is currently unavailable. Therefore, in this study, we aimed to investigate the protective effects of the GLP-1 analogue liraglutide against lipotoxicity-induced oxidative stress in HepG2 cells and to elucidate the underlying mechanisms. HepG2 cells were cultured for 48 hours and treated with a free fatty acid (FFA) mixture: FFA mixture and liraglutide or FFA mixture, liraglutide, and exendin (9-39). Lipid accumulation was examined by oil red O staining. Oxidative stress was assessed by measuring the levels of intracellular reactive oxygen species using 2',7'-dichlorofluorescein diacetate and thiobarbituric acid-reactive substances, whereas antioxidant capacity was assessed by measuring the activity of superoxide dismutase and catalase. Expression of the nuclear factor erythroid-2-related factor 2 (NRF2) gene and the genes encoding antioxidant enzymes was analyzed using quantitative RT-PCR. Cellular and nuclear NRF2 expression levels were assessed using immunofluorescence cell staining and western blotting. Liraglutide treatment reduced high fat-induced lipid formation and the levels of oxidative stress markers and increased antioxidant enzyme activity in HepG2 cells. Liraglutide treatment increased the mRNA expression of NRF2 target genes, induced NRF2 nuclear translocation, and increased nuclear NRF2 levels without altering NRF2 mRNA expression. Collectively, these results indicate that liraglutide exhibits a protective effect against lipotoxicity-induced oxidative stress, possibly via modulation of NRF2 and expression of antioxidant enzymes in liver cells.

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