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We study theoretically the Josephson diode effect (JDE) when realized in a system composed of parallel-coupled double-quantum dots (DQDs) sandwiched between two semiconductor nanowires deposited on an s-wave superconductor surface. Due to the combined effects of proximity-induced superconductivity, strong Rashba spin-orbit interaction, and the Zeeman splitting inside the nanowires, a pair of Majorana bound states (MBSs) may possibly emerge at opposite ends of each nanowire. Different phase factors arising from the superconductor substrate can be generated in the coupling amplitudes between the DQDs and MBSs prepared at the left and right nanowires, and this will result in the Josephson current. We find that the critical Josephson currents in positive and negative directions are different from each other in amplitude within an oscillation period with respect to the magnetic flux penetrating through the system, a phenomenon known as the JDE. It arises from the quantum interference effect in this double-path device, and it can hardly occur in the system of one QD coupled to MBSs. Our results also show that the diode efficiency can reach up to 50%, but this depends on the overlap amplitude between the MBSs, as well as the energy levels of the DQDs adjustable by gate voltages. The present model is realizable within current nanofabrication technologies and may find practical use in the interdisciplinary field of Majorana and Josephson physics.
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We study the electron tunneling (ET) and local Andreev reflection (AR) processes in a quantum dot (QD) coupled to the left and right ferromagnetic leads with noncollinear ferromagnetisms. In particular, we consider that the QD is also side-coupled to a nanowire hosting Majorana bound states (MBSs) at its ends. Our results show that when one mode of the MBSs is coupled simultaneously to both spin-up and spin-down electrons on the QD, the height of the central peak is different from that if the MBS is coupled to only one spin component electrons. The ET and AR conductances, which are mediated by the dot-MBS hybridization, strongly depend on the angle between the left and right magnetic moments in the leads. Interaction between the QD and the MBSs will result in sign change of the angle-dependent tunnel magnetoresistance. This is very different from the case when the QD is coupled to regular fermonic mode, and can be used for detecting the existence of MBSs, a current challenge in condensed matter physics under extensive investigations.
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BACKGROUND: Increasing evidence suggests that leptin is involved in the pathology of autism spectrum disorder (ASD). In this study, our objective was to investigate the levels of leptin in the blood of children with ASD and to examine the overall profile of adipokine markers in ASD through meta-analysis. METHODS: Leptin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) kit, while adipokine profiling, including leptin, was performed via meta-analysis. Original reports that included measurements of peripheral adipokines in ASD patients and healthy controls (HCs) were collected from databases such as Web of Science, PubMed, and Cochrane Library. These studies were collected from September 2022 to September 2023 and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Standardized mean differences were calculated using a random effects model for the meta-analysis. Additionally, we performed meta-regression and explored heterogeneity among studies. RESULTS: Our findings revealed a significant increase in leptin levels in children with ASD compared to HCs (p = 0.0319). This result was consistent with the findings obtained from the meta-analysis (p < 0.001). Furthermore, progranulin concentrations were significantly reduced in children with ASD. However, for the other five adipokines analyzed, there were no significant differences observed between the children with ASD and HCs children. Heterogeneity was found among the studies, and the meta-regression analysis indicated that publication year and latitude might influence the results of the meta-analysis. CONCLUSIONS: These findings provide compelling evidence that leptin levels are increased in children with ASD compared to healthy controls, suggesting a potential mechanism involving adipokines, particularly leptin, in the pathogenesis of ASD. These results contribute to a better understanding of the pathology of ASD and provide new insights for future investigations.
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Adipocinas , Transtorno do Espectro Autista , Leptina , Humanos , Transtorno do Espectro Autista/sangue , Leptina/sangue , Criança , Adipocinas/sangue , Biomarcadores/sangueRESUMO
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target enzyme in albino herbicides. The inhibition of HPPD activity interferes with the synthesis of carotenoids, blocking photosynthesis and resulting in bleaching and necrosis. To develop herbicides with excellent activity, a series of 3-hydroxy-2-(6-substituted phenoxynicotinoyl)-2-cyclohexen-1-one derivatives were designed via active substructure combination. The title compounds were characterized via infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The structure of compound III-17 was confirmed via single-crystal X-ray diffraction. Preliminary tests demonstrated that some compounds had good herbicidal activity. Crop safety tests revealed that compound III-29 was safer than the commercial herbicide mesotrione in wheat and peanuts. Moreover, the compound exhibited the highest inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD), with a half-maximal inhibitory concentration of 0.19 µM, demonstrating superior activity compared with mesotrione (0.28 µM) in vitro. A three-dimensional quantitative structure-activity relationship study revealed that the introduction of smaller groups to the 5-position of cyclohexanedione and negative charges to the 3-position of the benzene ring enhanced the herbicidal activity. A molecular structure comparison demonstrated that compound III-29 was beneficial to plant absorption and conduction. Molecular docking and molecular dynamics simulations further verified the stability of the complex formed by compound III-29 and AtHPPD. Thus, this study may provide insights into the development of green and efficient herbicides.
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4-Hidroxifenilpiruvato Dioxigenase , Arabidopsis , Desenho de Fármacos , Inibidores Enzimáticos , Herbicidas , 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Arabidopsis/efeitos dos fármacos , Arabidopsis/enzimologia , Proteínas de Arabidopsis/antagonistas & inibidores , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/metabolismo , Cicloexanonas/química , Cicloexanonas/farmacologia , Cicloexanonas/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Herbicidas/síntese química , Herbicidas/farmacologia , Cetonas/síntese química , Cetonas/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triticum/efeitos dos fármacosRESUMO
As an emerging environmental pollutant, microplastics have attracted much attention, but the sources and health hazards of atmospheric microplastics (AMPs) remain unclear. In order to explore the distribution characteristics, assess the risk of human respiratory exposure, and analyze the sources of AMPs in different functional areas of Yichang City, AMPs samples from 16 observation points were collected and analyzed, and the HYSPLIT model was used. The results showed that the main shapes of AMPs in Yichang City were fiber, fragment, and film, and six colors were observed including transparent, red, black, green, yellow, and purple. The smallest size was 10.42 µm, and the largest was 4761.42 µm. The deposition flux of AMPs was (4400±474) n·(m2·d)-1. The types of APMs were polyester fiber (PET), acrylonitrile-butadiene-styrene copolymer (ABS), polyamide (PA), rubber (Rubber), polyethylene (PE), cellulose acetate (CA), and polyacrylonitrile (PAN). The order of the subsidence flux in each functional area was as follows:urban residential area>agricultural production area>landfill>chemical industrial park>town residential area. The human respiratory exposure risk assessment models showed that the daily intake of AMPs (EDI) for adults and children in urban residential areas was higher than in town residential areas. The atmospheric backward trajectory simulation showed that the AMPs in the districts and counties of Yichang City mainly came from the surrounding areas via short-distance transportation. This study provided basic data support for the research on AMPs in the middle reaches of the Yangtze River and was of great significance for the traceability and health risk research of AMPs pollution.
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Acrilonitrila , Microplásticos , Adulto , Criança , Humanos , Plásticos , Borracha , AgriculturaRESUMO
We investigate the behavior of the Josephson current in a system composed of a quantum dot (QD) sandwiched between two nanowires by using the nonequilibrium Green's function technique. We consider that the nanowires are in proximity to s-wave superconducror substrates, and Majorana bound states (MBSs) are induced at their ends. It is also assumed that the two nanowires are not aligned in the same orientation, but form a bent angle with respect to each other. It is found that when only one spin state on the QD is coupled to the left nanowire, the Josephson current is the typical sinusoidal function of the phase difference between the two nanowires. If both spin states hybridize to the MBSs with equal coupling strengths, the Josephson current then is not a sinusoidal function of the phase difference. In particular, when the bent angle between the two nanowires is π/2 and the two modes of the MBSs in each nanowire are decoupled from each other, the Josephson current is enhanced by about twenty times in magnitude as compared to the former case. Moreover, the simultaneously enhanced currents of the two spin directions are of the same magnitude but flow in opposite directions and they induce a large pure spin current. Our results also show that this abnormally enhanced Josephson current will be suppressed by a vertical magnetic field applied to the QD.
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BACKGROUND: Increased torsional deformity of femur is one of the most important factors in recurrent patellofemoral instability. And distal femoral derotational osteotomy is an effective treatment option in patients with increased femoral torsional deformity. However, groin pain is a rare complication after femoral derotational osteotomy. CASE PRESENTATION: The patient was a 23-year-old female suffering from anterior knee pain and patellar instability in her left leg. Continuous CT scans of the hip, knee, and ankle were performed and the femoral anteversion was 44.99°. Considering the significant enlargement of the femoral internal torsion which may contribute most for dislocation of patella, we did a derotational osteotomy of distal femur. The anterior knee pain and patellar instability were resolved after surgery. The femoral internal torsion angle was corrected to 21.47°. But she developed left hip pain in the groin area which she had never encountered before 1 year after the surgery. We believed that the hip pain was closely related to the surgery. And the imaging and follow-up partly confirmed this. CONCLUSIONS: The situation of the hip joint should be carefully evaluated before doing derotational osteotomy in recurrent patellofemoral instability and patient should be informed that derotational osteotomy may cause hip pain. Clinical studies are needed to further clarify the impact of derotational osteotomy on the hip.
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Doenças Ósseas , Instabilidade Articular , Articulação Patelofemoral , Humanos , Feminino , Adulto Jovem , Adulto , Articulação Patelofemoral/diagnóstico por imagem , Articulação Patelofemoral/cirurgia , Instabilidade Articular/etiologia , Instabilidade Articular/cirurgia , Fêmur/cirurgia , Artralgia , Osteotomia/métodos , Dor PélvicaRESUMO
BACKGROUND: Elderly rheumatoid arthritis (ERA) population faces multiple treatment dilemma. Here we aim to investigate if Gancao Nourishing-Yin decoction (GCNY) added to methotrexate (MTX) exhibit better effects in an ERA mice model. METHODS: ERA mice model was established by adding D-galactose (Dgal) to collagen-induced arthritis (CIA) mice. The model was then assigned into control group (CIA + Dgal), MTX treatment group (MTX), GCNY treatment group (GCNY), and integrative treatment group (MTX + GCNY). Pathological scoring was performed to evaluate the severity between the groups. Proteomic analysis was applied to investigate the secretory phenotype of the ERA mouse model and the underlying mechanism of GCNY, MTX and their combination. Representative cytokines related to proteomic results were further validated by ELISAs. RESULTS: CIA + Dgal mice showed more aggressive joints damage than the CIA mice. Besides changes in the inflammatory pathway such as Pi3k-Akt signaling pathway in both model, differential expressed proteins (DEPs) indicated metabolism-related pathways were more obvious in CIA + Dgal mice. Low-dose MTX failed to show pathological improvement in CIA + Dgal mice, while GCNY improved joints damage significantly. Besides down-regulated inflammation-related targets, GCNY-regulated DEPs (such as Apoc1 ~ 3, Grk2 and Creb3l3) were broadly enriched in metabolism-related pathways. MTX + GCNY showed the best therapeutic effect, and the DEPs enriched in a variety of inflammatory,metabolism and osteoclast differentiation signaling pathway. Notably, MTX + GCNY treatment up-regulated Dhfr, Cbr1, Shmt1 involved in folic acid biosynthesis and anti-folate resistance pathways indicated a coincidence synergic action. ELISAs confirmed CPR and Akt that elevated in CIA + Dgal mice were significantly ameliorated by treatments, and adding on GCNY elevated folic acid levels and its regulator Dhfr. CONCLUSION: Aging aggravated joints damage in CIA, which probably due to metabolic changes rather than more severe inflammation. GCNY showed significant effects in the ERA mice model especially when integrated with MTX to obtain a synergic action.
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BACKGROUND: Surgical transepicondylar axis (sTEA) is frequently used for positioning of femoral component rotation in total knee arthroplasty (TKA). Previous studies showed that intraoperative identification of sTEA was not reliable. While surgeons or engineers need to identify sTEA with three-dimensional (3D) computer-aid techniques pre- or intraoperatively, the reproducibility of sTEA identification on preoperative 3D images has not been explored yet. This study aimed to investigate the reproducibility of identifying sTEA in preoperative planning based on computed tomography (CT). METHODS: Fifty-nine consecutive patients (60 knees involved) who received TKA in our center from April 2019 to June 2019 were included in this study. Six experienced TKA surgeons identified sTEA three times on 3D model established on the basis of knee CT data. The projection angle of each sTEA and the posterior condyle axis on the transverse plane were measured and analyzed. RESULTS: The overall intra-observer reproducibility was moderate. The median intra-observer variation was 1.27°, with a maximum being up to 14.07°. The median inter-observer variation was 1.24°, and the maximum was 11.47°. The overall intra-class correlation coefficient (ICC) for inter-observer was 0.528 (95% CI 0.417, 0.643). CONCLUSION: The identification of sTEA on a 3D model established on the basis of knee CT data may not be reliable. Combined with the previous cadaveric and surgical studies, caution should be exercised in determining femoral component rotation by referencing sTEA both preoperatively and intraoperatively. LEVEL OF EVIDENCE: III.
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Colletotrichum species are important plant pathogens, causing anthracnose in virtually every crop grown throughout the world. However, little is known about the species that infect watermelon. A total of 526 strains were isolated from diseased watermelon samples of eight major watermelon growing provinces in China. Phylogenetic analyses using seven loci (ITS, gadph, chs-1, his3, act, tub2, and gs) coupled with morphology of 146 representative isolates showed that they belonged to 12 known species of Colletotrichum, including C. aenigma, C. chlorophyti, C. fructicola, C. jiangxiense, C. karstii, C. magnum, C. nymphaeae, C. nigrum, C. orbiculare, C. plurivorum, C. sojae, and C. truncatum and three new species, here described as C. citrulli, C. kaifengense, and C. qilinense. Colletotrichum orbiculare was the dominant species. Pathogenicity tests revealed that all isolates of the species described above were pathogenic, with C. magnum and C. kaifengense being the most aggressive to leaves and fruits, respectively. This is the first report of C. aenigma, C. chlorophyti, C. fructicola, C. jiangxiense, C. nymphaeae, C. nigrum, C. plurivorum, and C. sojae on watermelon. These findings shed light on the Colletotrichum spp. involved in watermelon anthracnose and provide useful information for implementing effective control of watermelon anthracnose in China.
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OBJECTIVE: This study explored whether robotic arm-assisted total knee arthroplasty (RATKA) has the advantage of restoring femoral rotational alignment compared to conventional total knee arthroplasty (COTKA). METHODS: Sixty patients (45 women and 15 men) attending our department from May 2019 to December 2020 were selected and divided into two groups, with 30 patients in each group, according to whether they underwent COTKA or RATKA. Femoral rotational alignment results, such as, posterior condylar angle (PCA), patella transverse axis-femoral transepicondylar axis angle (PFA), radiological findings, such as, hip-knee-ankle angle (HKA), lateral distal femoral angle (LDFA), and medial proximal tibial angle (MPTA), and operative data (operation time, intraoperative blood loss, tourniquet time, and length of stay (LOS), and clinical outcomes, such as maximum knee flexion angle (MKFA), Knee Society Score (KSS), and Western Ontario Mac Master University Index Score (WOMAC) were compared within and between the two groups. RESULTS: PCA and PFA in the RATKA group were (0.6 ± 0.3)° and (0.9 ± 0.3)°, respectively, which were smaller than (1.5 ± 2.0)° and (3.1 ± 1.1)° in the COTKA group (P < 0.05), and were closer to 0°; the differences in HKA, LDFA, and MPTA were not statistically significant. With the exception of the LDFA, the HKA, MPTA, PCA, and PFA improved in both groups after surgery (P < 0.05). The blood loss and the LOS of RATKA group were 192.3 ± 23.1 mL and 8.2 ± 1.4 days, which were less than 203.7 ± 29.8 mL and 9.3 ± 1.1 days of the COTKA group, but the operation time showed no statistically significant difference, and the tourniquet time was longer (P < 0.05). The MKFA in the RATKA group was (123.0 ± 3.7)°, which was greater than (116.3 ± 4.6)° in the COTKA group (P < 0.05). In terms of scores, the postoperative results were better than the preoperative results in both groups (P < 0.05). However, there was no statistically significant difference between the groups. CONCLUSION: The accuracy of femoral rotational alignment reconstructed achieved by RATKA is significantly better than that of COTKA and is more conducive to the recovery of knee flexion function after surgery; although RATKA reduces intraoperative blood loss and postoperative LOS, the short-term clinical efficacy comparison has not yet demonstrated the advantages of robotic technology, and a more optimized design is needed to improve the efficiency of RATKA surgery.
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Artroplastia do Joelho , Osteoartrite do Joelho , Robótica , Artroplastia do Joelho/métodos , Perda Sanguínea Cirúrgica , Feminino , Humanos , Articulação do Joelho/cirurgia , Masculino , Osteoartrite do Joelho/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: This study aimed to compare the short-term clinical results of slight femoral under-correction with neutral alignment in patients with preoperative varus knees who underwent total knee arthroplasty. METHODS: The medical records and imaging data were retrospectively collected from patients who had undergone total knee arthroplasty in our hospital from January 2016 to June 2019. All patients had varus knees preoperatively. Upon 1:1 propensity score matching, 256 patients (256 knees) were chosen and divided into a neutral alignment group (n=128) and an under-correction group (n=128). The patients in the neutral group were treated with the neutral alignment. In the under-correction group, the femoral mechanical axis had a 2° under-correction. The operative time, tourniquet time and the length of hospital stay in the two groups were recorded. The postoperative hip-knee-ankle angle, frontal femoral component angle and frontal tibial component angle were measured. Patient-reported outcome measures were also compared. RESULTS: The operative time, tourniquet time and the length of hospital stay in the under-correction group were significantly shorter than the neutral alignment group (P<0.05). At the 2-year follow-up, the under-correction group had a larger varus alignment (P<0.05) and a larger frontal femoral component angle (P<0.05), and the frontal tibial component angles of the two groups were comparable. Compared with the neutral alignment group, the slight femoral under-correction group had significantly better patient-reported outcome measures scores (P<0.05). CONCLUSION: For varus knees treated with total knee arthroplasty, alignment with a slight femoral under-correction has advantages over the neutral alignment in terms of the shorter operative time and better short-term clinical results. LEVEL OF EVIDENCE: III.
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Widespread soil acidification due to atmospheric acid deposition and agricultural fertilization may greatly accelerate soil carbonate dissolution and CO2 release. However, to date, few studies have addressed these processes. Here, we use meta-analysis and nationwide-survey datasets to investigate changes in soil inorganic carbon (SIC) stocks in China. We observe an overall decrease in SIC stocks in topsoil (0-30 cm) (11.33 g C m-2 yr-1) from the 1980s to the 2010s. Total SIC stocks have decreased by â¼8.99 ± 2.24% (1.37 ± 0.37 Pg C). The average SIC losses across China (0.046 Pg C yr-1) and in cropland (0.016 Pg C yr-1) account for â¼17.6%-24.0% of the terrestrial C sink and 57.1% of the soil organic carbon sink in cropland, respectively. Nitrogen deposition and climate change have profound influences on SIC cycling. We estimate that â¼19.12%-19.47% of SIC stocks will be further lost by 2100. The consumption of SIC may offset a large portion of global efforts aimed at ecosystem carbon sequestration, which emphasizes the importance of achieving a better understanding of the indirect coupling mechanisms of nitrogen and carbon cycling and of effective countermeasures to minimize SIC loss.
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LncRNAs exert comprehensive effects in regulating the initiation and deterioration of hepatocellular carcinoma (HCC). However, the specific expression profiles and functional mechanisms of LINC00536 in HCC need to be disclosed. The study is intended to clarify the leverage of LINC00536 in HCC and investigate the potential mechanisms for the regulatory role of LINC00536 in the progression of HCC. In our study, LINC00536 was overexpressed in tumor samples of HCC patients and was related to poor prognosis. LINC00536 knockdown impaired cell viability, proliferation, migration, and invasion. LINC00536 can directly bind with miR-203b-5p, trimming the miR-203b-5p expression levels. VEGFA designates as a target of miR-203b-5p. Rescue research indicated that the miR-203b-5p inhibition or VEGFA overexpression could reverse the impaired cell phenotypes induced by LINC00536 knockdown. The in vivo experiments upheld the LINC00536/miR-203b-5p/VEGFA axis in HCC. Conclusively, LINC00536 could promote HCC deterioration via tuning the miR-203b-5p/VEGFA axis. This research may provide theoretical evidence for LINC00536 to get a gratifying therapeutic target for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Fator A de Crescimento do Endotélio VascularRESUMO
This article focuses on engineering Corynebacterium glutamicum to produce L-lysine efficiently from starch using combined method of "classical breeding" and "genome breeding." Firstly, a thermo-tolerable L-lysine-producing C. glutamicum strain KT45-6 was obtained after multi-round of acclimatization at high temperature. Then, amylolytic enzymes were introduced into strain KT45-6, and the resultant strains could use starch for cell growth and L-lysine production except the strain with expression of isoamylase. In addition, co-expression of amylolytic enzymes showed a good performance in starch degradation, cell growth and L-lysine production, especially co-expression of α-amylase (AA) and glucoamylase (GA). Moreover, L-lysine yield was increased by introducing AA-GA fusion protein (i.e., strain KT45-6S-5), and finally reached to 23.9 ± 2.3 g/L in CgXIIIPM-medium. It is the first report of an engineered L-lysine-producing strain with maximum starch utilization that may be used as workhorse for producing amino acid using starch as the main feedstock. KEY POINTS: ⢠Thermo-tolerable C. glutamicum was obtained by temperature-induced adaptive evolution. ⢠The fusion order between AA and GA affects the utilization efficiency of starch. ⢠C. glutamicum with starch utilization was constructed by optimizing amylases expression.
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Corynebacterium glutamicum , Corynebacterium glutamicum/genética , Corynebacterium glutamicum/metabolismo , Fermentação , Lisina/metabolismo , Engenharia Metabólica , Amido/metabolismo , Zea mays/metabolismoRESUMO
With the widespread application of next-generation sequencing(NGS), especially 16 S rRNA and shotgun sequencing, researchers are no longer troubled with massive data on the gut microbiota, and the correlation between the gut microbiota and the brain(central nervous system) has been gradually revealed. Research on the microbiota-gut-brain axis(MGBA) based on the gut microbiota have provided insights into the exploration of the pathogenesis and risk factors of ischemic stroke(IS), a cerebrovascular disease with high disability and mortality rates, and also facilitate the selection of therapeutic targets of this class of drugs. This study reviewed the application of NGS in the study of gut microbiota and the research progress of MGBA in recent years and systematically collated the research papers on the correlation between IS and gut microbiota. Furthermore, from the bi-directional regulation of MGBA, this study also discussed the high-risk factors of IS under the dysregulation of gut microbiota and the pathophysiological changes of gut microbiota after the occurrence of IS and summarized the related targets to provide a reliable reference for the therapeutic research of IS from the gut microbiota.
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Microbioma Gastrointestinal , AVC Isquêmico , Acidente Vascular Cerebral , Encéfalo , Eixo Encéfalo-Intestino , Humanos , Acidente Vascular Cerebral/genéticaRESUMO
The protein p53 is one of the most important tumor suppressors, responding to a variety of stress signals. Mutations in p53 occur in about half of human cancer cases, and dysregulation of the p53 function by epigenetic modifiers and modifications is prevalent in a large proportion of the remainder. PRMT1 is the main enzyme responsible for the generation of asymmetric-dimethylarginine, whose upregulation or aberrant splicing has been observed in many types of malignancies. Here, we demonstrate that p53 function is regulated by PRMT1 in breast cancer cells. PRMT1 knockdown activated the p53 signal pathway and induced cell growth-arrest and senescence. PRMT1 could directly bind to p53 and inhibit the transcriptional activity of p53 in an enzymatically dependent manner, resulting in a decrease in the expression levels of several key downstream targets of the p53 pathway. We were able to detect p53 asymmetric-dimethylarginine signals in breast cancer cells and breast cancer tissues from patients, and the signals could be significantly weakened by silencing of PRMT1 with shRNA, or inhibiting PRMT1 activity with a specific inhibitor. Furthermore, PRMT1 inhibitors significantly impeded cell growth and promoted cellular senescence in breast cancer cells and primary tumor cells. These results indicate an important role of PRMT1 in the regulation of p53 function in breast tumorigenesis.
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BACKGROUND: Warfarin treatment requires frequent monitoring of INR (international normalized ratio) to adjust dosage in a therapeutic range. In China, patients living in small towns usually go to tertiary hospitals to get warfarin monitoring and dosing, resulting in low frequencies of follow-ups and high incidence of complications. Influenced by the COVID-19 pandemic, patients on warfarin have further reduced their visits to healthcare institutions. While patient self-testing (PST) via using a point-of-care testing device for INR measuring at home has been widely used in developed countries and demonstrated improved clinical outcomes compared to usual care in clinics, it is rarely applied in developing countries, including China. This proposed study will develop and assess the "Safe Multidisciplinary App-assisted Remote patient-self-Testing (SMART) model" for warfarin home management in China during the COVID-19 pandemic. METHODS: This is a multi-center randomized controlled trial. We will carry out the study in three county hospitals, three small tertiary hospitals and three large tertiary hospitals with anticoagulation clinics in Hunan province of China. Eligible patients will be randomly assigned to the SMART model group (n = 360) or the control group (usual care clinic group, n = 360; anticoagulation clinic group, n = 120). Patients in the SMART model group do PST at home once every two to 4 weeks. Controls receive usual care in the clinics. All the patients will be followed up through outpatient clinics, phone call or online interviews at the 3rd, 6th, 9th and 12th month. The percentage of time in therapeutic range (TTR), incidence of warfarin associated major bleeding and thromboembolic events and costs will be compared between the SMART model group and control groups. DISCUSSION: Patients in the SMART model group would show improved TTR, lower incidence of complications and better quality of life compared to the control groups. Our design, implementation and usage of the SMART model will provide experience and evidence in developing a novel model for chronic disease management to solve the problem of healthcare service maldistribution, an issue particularly obvious in developing countries during the COVID-19 pandemic. TRIAL REGISTRATION: ChiCTR, ChiCTR 2000038984 . Registered 11 October, 2020.
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COVID-19 , Aplicativos Móveis , Anticoagulantes/efeitos adversos , Humanos , Coeficiente Internacional Normatizado , Estudos Multicêntricos como Assunto , Pandemias/prevenção & controle , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Autoteste , Varfarina/efeitos adversosRESUMO
INTRODUCTION: Adefovir plus entecavir (ADV+ETV) rescue therapy in ETV-resistant patients with chronic hepatitis B virus (HBV) infection is suboptimal in some patients. This study aims to elucidate the evolutionary characteristics of drug-resistant HBV mutants and their association with clinical responses in such patients. METHODOLOGY: Thirty-seven ETV-resistant patients were enrolled, among whom twelve had an inadequate virological response to ADV+ETV rescue therapy. The clonal sequence (³ 20 clones/sample) of HBV reverse transcriptase gene was performed to identify the resistance mutations. Phenotypic analysis was performed to evaluate the replication capacity and drug susceptibility of the mutants. RESULTS: ETV-resistant mutants were continuously detected in 10 of the 12 patients, and multidrug-resistant (MDR) mutants, including a novel strain (rtL180M+A181V+T184A+S202G+M204V), were detected in two patients. Seven of the 12 patients who subsequently received tenofovir (TDF)-based therapy for 38 (23-60) months all achieved undetectable HBV DNA after treatment, and ETV-resistant mutants converted to wild-type in the four patients' samples. In contrast, the other five patients who did not achieve an adequate virological response had remaining of ETV-resistant mutants. The novel MDR strain exhibited multiple resistances to LAM, ADV, and ETV, and 11.2-fold lower susceptibility to TDF. CONCLUSIONS: This study is the first to demonstrate that MDR HBV mutations may contribute to the poor efficacy of ADV+ETV combination therapy in ETV-resistant patients. Moreover, a novel MDR HBV strain was identified. Our results indicate that a TDF-based rescue therapy would be effective for the treatment of the refractory cases.