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1
Chandrashekaran, Murali, and Beth A. Walker. "Meta-Analysis with Heteroscedastic Effects." Journal of Marketing Research 30, no. 2 (May 1993): 246–55. http://dx.doi.org/10.1177/002224379303000209.
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To enhance the utility of meta-analysis as an integrative tool for marketing research, heteroscedastic MLE (HMLE), a maximum-likelihood-based estimation procedure, is proposed as a method that overcomes heteroscedasticity, a problem known to impair OLS estimates and threaten the validity of meta-analytic findings. The results of a Monté Carlo simulation experiment reveal that, under a wide range of heteroscedastic conditions, HMLE is more efficient and powerful than OLS and achieves these performance advantages without inflating type I error. Further, the relative performance of HMLE increases as heteroscedasticity becomes more severe. An empirical analysis of a meta-analytic dataset in marketing confirmed and extended these findings by illustrating how the enhanced efficiency and power of HMLE improve the ability to detect moderator variables and by demonstrating how the theoretical generalizations emerging from a meta-analysis are affected by the choice of the analytic procedure.
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Zhan, Chesheng, Jian Han, Lei Zou, Fubao Sun, and Tiejun Wang. "Heteroscedastic and symmetric efficiency for hydrological model evaluation criteria." Hydrology Research 50, no. 5 (June 20, 2019): 1189–201. http://dx.doi.org/10.2166/nh.2019.121.
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Abstract Evaluation criteria play a key role in assessing the performances of hydrological models. Most previous criteria are based on the standard least square method, which assumes model residuals to be homoscedastic and is, therefore, not suitable for assessing cases with heteroscedastic residuals. Here, we compared a heteroscedastic and symmetric efficiency (HSE) criterion with the Nash–Sutcliffe efficiency (NSE) and the heteroscedastic maximum-likelihood estimator (HMLE) by running a monthly water balance model with four parameters (i.e., the abcd model) in 138 basins located in the continental United States derived from the Model Parameter Estimation Experiment dataset. The results show that compared to the NSE, the HSE and HMLE are both more effective for stabilizing variance and producing more uniform performances with flow magnitude, and the latter is slightly more effective than the former on stabilizing the residual heteroscedasticity, with the aid of an additional parameter.
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Reche-Soto, Pedro, Daniel Rojas-Valverde, Alejandro Bastida-Castillo, Carlos D. Gómez-Carmona, Markel Rico-González, Luiz H. Palucci Vieira, Luca Paolo Ardigò, and José Pino-Ortega. "Using Ultra-Wide Band to Analyze Soccer Performance through Load Indicators during a Full Season: A Comparison between Starters and Non-Starters." Applied Sciences 12, no. 24 (December 10, 2022): 12675. http://dx.doi.org/10.3390/app122412675.
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The objectives of this study are: (1) to compare match load demands through load indicators between starters and substitutes, and (2) analyze the degree of correlation in the variables analyzed in this investigation. Twenty-two semi-professional soccer players were analyzed during a full season’s 38 official matches. Participants were assigned to two different groups according to their participation in the game: (a) starting-up players (≥90 min played) vs. substitute players (≥45 min played in the second half). Statistical analysis was performed by using Mann–Whitney U test to conduct pairwise comparison and Spearman correlation to demands correlation in each group. Significant differences in both absolute and relative variables in player load (P, p < 0.01; p < 0.01), metabolic power (MP, p < 0.01; p = 0.15), equivalent distance index (EDI, p = 0.87; p < 0.01), dynamic stress load (DSI, p < 0.01; p = 0.977), energy expenditure (EE, p < 0.01; p < 0.01), high metabolic load events (HMLE, p < 0.01; p < 0.01), and high metabolic load distance (HMLD, p < 0.01; p = 0.09). Overall, high direct correlations in the starting-up group in absolute and relative demands of PL, PM, HMLD, EE, and DSL were found, as well as high inverse correlation in the substitute group in all variables, excluding DSL and HMLD. In conclusion, the absolute differences found suggested a different training load management during training sessions.
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Libring, Sarah, Aparna Shinde, Miad Boodaghidizaji, Alexandra Plummer, Arezoo Ardekani, Michael Wendt, and Luis Solorio. "4168 Understanding ECM-Based Drug Resistivity in Breast Cancer." Journal of Clinical and Translational Science 4, s1 (June 2020): 113–14. http://dx.doi.org/10.1017/cts.2020.346.
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OBJECTIVES/GOALS: Cell-cell (CC) and cell-matrix interactions (CM) are known to affect drug sensitivity of cancer cells, but are not effectively recapitulated using 2D platforms. This research aims to determine how cell and matrix interactions confer drug resistivity in 3 distinct culturing models: 2D (no CM/limited CC), 3D spheroids (CC) and 3D fibronectin (both). METHODS/STUDY POPULATION: We examined four breast cancer cell types. The cells were derived from a nonmetastatic primary tumor (HMLE-E2) or overt bone-metastasis (BM). Transglutaminase 2 (TGM2), a matrix crosslinking protein, is overexpressed in metastatic bone tumors and may play a key role in matrix-conferred drug resistivity. In a gain-of-function model, TGM2 was upregulated in HMLE-E2 cells and compared to shTGM2 knockdown BM cells. Growth rates were analyzed using metabolic activity over 8 days, and drug sensitivity to Neratinib (0-1000 nM) was analyzed via cell titer. To account for the different transport properties of the 3 distinct culture environments, we developed a mathematical model for each condition, allowing us to normalize the drug sensitivity results across models to effectively compare true biological resistivity. RESULTS/ANTICIPATED RESULTS: We observed that increased cellular levels of TGM2 significantly increase the growth rate and drug resistivity of cells on fibronectin matrices. Interestingly, in 2D cultures, TGM2 expression was correlated with higher Neratinib resistivity but did not affect growth rates. In spheroid models without a significant matrix component, that rely solely on cell-cell junctions, high levels of TGM2 were correlated with lower survival rates. Lower levels of TGM2 are correlated with a more epithelial phenotype, and using our mathematical model we have identified significant transport differences between high and low TGM2 spheroids. We theorize that the low TGM2 spheroids have denser packing, which lowers the rate of diffusion and, thus reduces the effective concentration of the drug to the majority of the cells. DISCUSSION/SIGNIFICANCE OF IMPACT: Our studies indicate that the cellular response to drugs can be altered by changes in both transport properties of the tissue and the CM interactions. By systematically investigating the effects of CC interactions and CM interactions, we can use mathematical models to delineate physical means of drug resistivity from a biologically driven resistance.
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Weiss, Kerstin, and Robert T. Simpson. "High-Resolution Structural Analysis of Chromatin at Specific Loci: Saccharomyces cerevisiae Silent Mating Type Locus HMLα." Molecular and Cellular Biology 18, no. 9 (September 1, 1998): 5392–403. http://dx.doi.org/10.1128/mcb.18.9.5392.
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ABSTRACT Genetic studies have suggested that chromatin structure is involved in repression of the silent mating type loci in Saccharomyces cerevisiae. Chromatin mapping at nucleotide resolution of the transcriptionally silent HMLα and the activeMATα shows that unique organized chromatin structure characterizes the silent state of HMLα. Precisely positioned nucleosomes abutting the silencers extend over the α1 and α2 coding regions. The HO endonuclease recognition site, nuclease hypersensitive at MATα, is protected atHMLα. Although two precisely positioned nucleosomes incorporate transcription start sites at HMLα, the promoter region of the α1 and α2 genes is nucleosome free and more nuclease sensitive in the repressed than in the transcribed locus. Mutations in genes essential for HML silencing disrupt the nucleosome array near HML-I but not in the vicinity of HML-E, which is closer to the telomere of chromosome III. At the promoter and the HO site, the structure of HMLα in Sir protein and histone H4 N-terminal deletion mutants is identical to that of the transcriptionally active MATα. The discontinuous chromatin structure of HMLα contrasts with the continuous array of nucleosomes found at repressed a-cell-specific genes and the recombination enhancer. Punctuation at HMLα may be necessary for higher-order structure or karyoskeleton interactions. The unique chromatin architecture of HMLα may relate to the combined requirements of transcriptional repression and recombinational competence.
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Bystricky, Kerstin, Haico Van Attikum, Maria-Dolores Montiel, Vincent Dion, Lutz Gehlen, and Susan M. Gasser. "Regulation of Nuclear Positioning and Dynamics of the Silent Mating Type Loci by the Yeast Ku70/Ku80 Complex." Molecular and Cellular Biology 29, no. 3 (December 1, 2008): 835–48. http://dx.doi.org/10.1128/mcb.01009-08.
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ABSTRACT We have examined the hypothesis that the highly selective recombination of an active mating type locus (MAT) with either HMLα or HMR a is facilitated by the spatial positioning of relevant sequences within the budding yeast (Saccharomyces cerevisiae) nucleus. However, both position relative to the nuclear envelope (NE) and the subnuclear mobility of fluorescently tagged MAT, HML, or HMR loci are largely identical in haploid a and α cells. Irrespective of mating type, the expressed MAT locus is highly mobile within the nuclear lumen, while silent loci move less and are found preferentially near the NE. The perinuclear positions of HMR and HML are strongly compromised in strains lacking the Silent information regulator, Sir4. However, HMLα, unlike HMR a and most telomeres, shows increased NE association in a strain lacking yeast Ku70 (yKu70). Intriguingly, we find that the yKu complex is associated with HML and HMR sequences in a mating-type-specific manner. Its abundance decreases at the HMLα donor locus and increases transiently at MAT a following DSB induction. Our data suggest that mating-type-specific binding of yKu to HMLα creates a local chromatin structure competent for recombination, which cooperates with the recombination enhancer to direct donor choice for gene conversion of the MAT a locus.
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Li, Xiu Juan, Zhao Jun Ren, Jin Hai Tang, and Qiao Yu. "Exosomal MicroRNA MiR-1246 Promotes Cell Proliferation, Invasion and Drug Resistance by Targeting CCNG2 in Breast Cancer." Cellular Physiology and Biochemistry 44, no. 5 (2017): 1741–48. http://dx.doi.org/10.1159/000485780.
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Background/Aims: Treatment of breast cancer remains a clinical challenge. This study aims to validate exosomal microRNA-1246 (miR-1246) as a serum biomarker for breast cancer and understand the underlying mechanism in breast cancer progression. Methods: The expression levels of endogenous and exosomal miRNAs were examined by real time PCR, and the expression level of the target protein was detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study their uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-1246 was estimated by invasion assay and cell viability assay. Results: In this study, we demonstrate that exosomes carrying microRNA can be transferred among different cell lines through direct uptake. miR-1246 is highly expressed in metastatic breast cancer MDA-MB-231 cells compared to non-metastatic breast cancer cells or non-malignant breast cells. Moreover, miR-1246 can suppress the expression level of its target gene, Cyclin-G2 (CCNG2), indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could enhance the viability, migration and chemotherapy resistance of non-malignant HMLE cells. Conclusions: Together, our results support an important role of exosomes and exosomal miRNAs in regulating breast tumor progression, which highlights their potential for applications in miRNA-based therapeutics.
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Singh, Vishal, Keshav Kumar Jha, Jyothsna K. M, Rekha V. Kumar, Varun Raghunathan, and Ramray Bhat. "Iduronate-2-Sulfatase-Regulated Dermatan Sulfate Levels Potentiate the Invasion of Breast Cancer Epithelia through Collagen Matrix." Journal of Clinical Medicine 8, no. 10 (September 30, 2019): 1562. http://dx.doi.org/10.3390/jcm8101562.
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Cancer epithelia show elevation in levels of sulfated proteoglycans including dermatan sulfates (DS). The effect of increased DS on cancer cell behavior is still unclear. We hypothesized that decreased expression of the enzyme Iduronate-2-sulfatase (IDS) can lead to increased DS levels, which would enhance the invasion of cancer cells. Breast cancer sections shows depleted IDS levels in tumor epithelia, when compared with adjacent untransformed breast tissues. IDS signals showed a progressive decrease in the non-transformed HMLE, transformed but non-invasive MCF-7 and transformed and invasive MDA-MB-231 cells, respectively, when cultured on Type 1 collagen scaffolds. DS levels measured by ELISA increased in an inverse-association with IDS levels. Knockdown of IDS in MCF-7 epithelia also increased the levels of DS. MCF-7 cells with depleted IDS expression, when imaged using two photon-excited fluorescence and second harmonic generation microscopy, exhibited a mesenchymal morphology with multiple cytoplasmic projections compared with epithelioid control cells, interacted with their surrounding matrix, and showed increased invasion through Type 1 collagen matrices. Both these traits were phenocopied when control MCF-7 cells were cultivated on Type 1 collagen gels polymerized in the presence of DS. In monolayer cultures, DS had no effect on MCF-7 migration. In the context of our demonstration that DS enhances the elastic modulus of Type 1 collagen gels, we propose that a decrease of IDS expression leads to accumulation within cancer epithelia of DS: the latter remodels the collagen around cancer cells leading to changes in cell shape and invasiveness through fibrillar matrix milieu.
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Luo, Haiqing, Chih-Yu Chen, Xiangyong Li, Xin Zhang, Chien-Wen Su, Yinghua Liu, Tinglan Cao, Lei Hao, Meng Wang, and Jing X. Kang. "Increased Lipogenesis is Critical for Self-Renewal and Growth of Breast Cancer Stem Cells: Impact of Omega-3 Fatty Acids." Stem Cells 39, no. 12 (September 17, 2021): 1660–70. http://dx.doi.org/10.1002/stem.3452.
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Abstract Aberrant lipid metabolism has recently been recognized as a new hallmark of malignancy, but the characteristics of fatty acid metabolism in breast cancer stem cells (BCSC) and potential interventions targeting this pathway remain to be addressed. Here, by using the in vitro BCSC models, mammosphere-derived MCF-7 cells and HMLE-Twist-ER cells, we found that the cells with stem cell-like properties exhibited a very distinct profile of fatty acid metabolism compared with that of their parental cancer cells, characterized by increased lipogenesis, especially the activity of stearoyl-CoA desaturase 1 (SCD1) responsible for the production of monounsaturated fatty acids, and augmented synthesis and utilization of the omega-6 arachidonic acid (AA). Suppression of SCD1 activity by either enzyme inhibitors or small interfering RNA (siRNA) knockdown strikingly limited self-renewal and growth of the BCSC, suggesting a key role for SCD1 in BCSC proliferation. Furthermore, elevated levels of SCD1 and other lipogenic enzymes were observed in human breast cancer tissues relative to the noncancer tissues from the same patients and correlated with the pathological grades. Interestingly, treatment of BCSC with omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, effectively downregulated the expression of the lipogenic enzymes and markedly suppressed BCSC self-renewal and growth. Dietary supplementation of nude mice bearing BCSC-derived tumors with omega-3 fatty acids also significantly reduced their tumor load. These findings have demonstrated that increased lipogenesis is critical for self-renewal and growth of BCSC, and that omega-3 fatty acids are effective in targeting this pathway to exert their anticancer effect.
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Zhao, Yingcheng, Xichuan Liu, Kang Pu, Jin Ye, and Minghao Xian. "Research on the Method of Rainfall Field Retrieval Based on the Combination of Earth–Space Links and Horizontal Microwave Links." Remote Sensing 14, no. 9 (May 6, 2022): 2220. http://dx.doi.org/10.3390/rs14092220.
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High-precision retrieval of rainfall over large areas is of great importance for the research of atmospheric detection and the social life. With the rapid development of communication satellite constellations and 5G communication networks, the use of widely distributed networks of earth–space links (ESLs) and horizontal microwave links (HMLs) to retrieve rainfall over large areas has great potential for obtaining high-precision rainfall fields and complementing traditional instruments of rainfall measurement. In this paper, we carry out the research of combining multiple ESLs with HMLs to retrieve rainfall fields. Firstly, a rainfall detection network for retrieving rainfall fields is built based on the atmospheric propagation model of ESL and HML. Then, the ordinary Kriging interpolation (OK) and radial basis function (RBF) neural network are applied to the reconstruction of rainfall fields. Finally, the performance of the joint network of ESLs and HMLs to retrieve rainfall fields in the area is validated. The results show that the joint network of ESLs and HMLs based on OK algorithm and RBF neural network is capable of retrieving the distribution of rain rates in different rain cells with high accuracy, and the root mean square error (RMSE) of retrieving the rain rates of real rainfall fields is lower than 0.56 mm/h, and the correlation coefficient (CC) is higher than 0.996. In addition, the CC for retrieving stratiform rainfall and convective rainfall by the joint network of ESLs and HMLs is higher than 0.949, indicating that the characteristics of the two different types of rainfall events can be accurately monitored.
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Coïc, Eric, Kaiming Sun, Cherry Wu, and James E. Haber. "Cell Cycle-Dependent Regulation of Saccharomyces cerevisiae Donor Preference during Mating-Type Switching by SBF (Swi4/Swi6) and Fkh1." Molecular and Cellular Biology 26, no. 14 (July 15, 2006): 5470–80. http://dx.doi.org/10.1128/mcb.02443-05.
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ABSTRACT Saccharomyces mating-type switching occurs through a double-strand break-initiated gene conversion event at MAT, using one of two donors located distantly on the same chromosome, HMLα and HMR a. MAT a cells preferentially choose HMLα, a decision that depends on the recombination enhancer (RE) that controls recombination along the left arm of chromosome III. We previously showed that an fhk1Δ mutation reduces HMLα usage in MAT a cells, but not to the level seen when RE is deleted. We now report that donor preference also depends on binding of the Swi4/Swi6 (SBF) transcription factors to an evolutionarily conserved SCB site within RE. As at other SCB-containing promoters, SBF binds to RE in the G1 phase. Surprisingly, Fkh1 binds to RE only in G2, which contrasts with its cell cycle-independent binding to its other target promoters. SBF and Fkh1 define two independent RE activation pathways, as deletion of both Fkh1 and SCB results in nearly complete loss of HML usage in MAT a cells. These transcription factors create an epigenetic modification of RE in a fashion that apparently does not involve transcription. In addition, the putative helicase Chl1, previously involved in donor preference, functions in the SBF pathway.
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Grandi, Nicole, Maria Paola Pisano, Sante Scognamiglio, Eleonora Pessiu, and Enzo Tramontano. "Comprehensive Analysis of HERV Transcriptome in HIV+ Cells: Absence of HML2 Activation and General Downregulation of Individual HERV Loci." Viruses 12, no. 4 (April 23, 2020): 481. http://dx.doi.org/10.3390/v12040481.
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Human endogenous retrovirus (HERV) expression is currently studied for its possible activation by HIV infection. In this context, the HERV-K(HML2) group is the most investigated: it has been proposed that HIV-1 infection can prompt HML2 transcription, and that HML2 proteins can affect HIV-1 replication, either complementing HIV or possibly influencing antiretroviral therapy. However, little information is available on the expression of other HERV groups in HIV infection. In the present study, we used a bioinformatics pipeline to investigate the transcriptional modulation of approximately 3250 well-characterized HERV loci, comparing their expression in a public RNA-seq profile, including a HIV-1-infected and a control T cell culture. In our pilot study, we found approximately 200 HERV loci belonging to 35 HERV groups that were expressed in one or both conditions, with transcripts per million (TPM) values from 1 to >500. Intriguingly, HML2 elements constituted only the 3% of expressed HERV loci, and in most cases (160) HERV expression was downregulated in the HIV-infected culture, showing from a 1- to 14-fold decrease as compared to uninfected cells. HERV transcriptome has been inferred de novo and employed to predict a total of about 950 HERV open reading frames (ORFs). These have been validated according to the coding potential and estimated abundance of the corresponding transcripts, leading to a set of 57 putative proteins potentially encoded by 23 HERV loci. Analysis showed that some individual loci have a coding potential that deserves further investigation. Among them, a HML6 provirus at locus 19q13.43 was predicted to produce a transcript showing the highest TPM among HERV-derived transcripts, being upregulated in HIV+ cells and inferred to produce Gag and Env puteins with possible biological activity.
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Gitlin, Scott D., Rafael Contreras Galindo, Mark H. Kaplan, and David M. Markovitz. "Role of Human Endogenous Retroviruses in Lymphoma Pathogenesis and a Possible Biomarker of Disease." Blood 112, no. 11 (November 16, 2008): 3751. http://dx.doi.org/10.1182/blood.v112.11.3751.3751.
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Abstract Actively replicating retroviruses entered hominid species millions of years ago and through mutations preventing replication now exist as 8% of the human genome. Active retroviral particles and antigens from the supposedly dormant human endogenous retrovirus, HERV-K (HML2), have been identified in several cancer cell lines. We have recently demonstrated very high RNA titers of HERV-K (HML2) in the plasma of HIV positive individuals by nucleic acid sequence-based amplification (NASBA) and RT-PCR. We now demonstrate very high HERV-K (HML2) RNA titers in the plasma of patients with HIV positive and HIV negative non-Hodgkin lymphoma (NHL) and in Hodgkin Disease (HD), but not in normal individuals. Different copies of HERV-K (HML-2) present throughout the human genome exist as Type 1 viruses which encode a new oncoprotein, NP9, or as Type 2 viruses which encode a functional envelope (env) and express the Rec oncoprotein. Both Types 1 and 2 viruses appear in NHLs but only Type 1 appears in the plasma of those with HD. HERV-K (HML2) Env and Gag proteins, Env and Gag RNA, and Reverse Transcriptase (RT) activity are isolated from patients with a variety of NHLs, but not in normal controls or in patients with non-malignant diseases. Viral titers dramatically decrease, up to an approximately 7.5 log drop, when patients with NHL or HD go into remission following treatment. To further establish the presence of functional viruses in NHL and HD, immuno-gold electron microscopy allowed demonstration of HERV-K (HML2) particles in the plasma of lymphoma patients. Preliminary analysis of the effect of antiretroviral agents on cell lines infected with HERV-K (HML2) demonstrate a drug class-specific reduction in viral expression at drug concentration levels that range from 0.125 – 1 mcg/mL. In conclusion, we have demonstrated evidence that human endogenous retroviruses are found in the plasma of patients with NHL and HD, suggesting that these viruses, previously presumed to be inactive, may play a role in lymphoma pathogenesis. The observation that viral expression parallels declines in disease activity with treatment of disease may allow use of HERV-K (HML2) expression as a biomarker of lymphoma activity. The role of the HERV-K (HML2)-encoded oncoproteins in disease pathogenesis is under study, as is the potential role of antiretroviral therapy for these malignancies.
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Lin, C. I., G. P. Livi, J. M. Ivy, and A. J. Klar. "Extragenic suppressors of mar2(sir3) mutations in Saccharomyces cerevisiae." Genetics 125, no. 2 (June 1, 1990): 321–31. http://dx.doi.org/10.1093/genetics/125.2.321.
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Abstract The silent mating-type genes (HML and HMR) of Saccharomyces cerevisiae are kept under negative transcriptional control by four trans-acting MAR (or SIR) loci. We have isolated extragenic suppressors of the mar2-1 mutation which, based on genetic complementation tests, define two additional loci involved in regulating the expression of HML and HMR. A strain with the genotype HMLa MAT alpha HMRa mar2-1 is sterile due to the simultaneous expression of a and alpha information. Two mutants exhibiting an alpha phenotype (which may result from the restoration of MAR/SIR repression) were isolated and genetically characterized. The mutations in these strains: (1) are recessive, (2) are capable of suppressing a mar2-deletion mutation, (3) are unlinked to MAT, (4) complement one another as well as the previously identified sum1-1 mutation, and (5) are not new alleles of the known MAR/SIR loci. We designate these new regulatory loci SUM2 and SUM3 (suppressor of mar). Unlike the sum1-1 mutation, suppression by sum2-1 and sum3-1 is mar2-locus specific. Both sum2-1 and sum3-1 affect the expression of a information at the HM loci. Transcript analysis shows a significant reduction in HMLa and HMRa gene transcription in mar2-1 sum2-1 and mar2-1 sum3-1 cells. Furthermore, we have found genetic evidence to suggest that mar2-1 sum2-1 cells exhibit only partial expression of silent alpha information. We conclude that the SUM2 and SUM3 gene products are required for expression of the HM loci and act downstream of the MAR2 (SIR3) gene function. Possible mechanisms for the action of the SUM gene products are discussed.
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Kastritis, Efstathios, Jana Jakubikova, Jake Delmore, Steffen Klippel, Douglas W. McMillin, Melissa Ooi, Hannah M. Jacobs, et al. "Preclinical Studies of Salinomycin In Multiple Myeloma (MM) Models: Targeting of Side Population (SP) Cells In the Context of Tumor – Microenvironment Interactions." Blood 116, no. 21 (November 19, 2010): 1574. http://dx.doi.org/10.1182/blood.v116.21.1574.1574.
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Abstract Abstract 1574 Cancer cells with stem cell-like features are a topic of intense research because their resistance to existing drugs is considered a culprit for relapses, even in patients with complete remission defined by clinical, biochemical and imaging parameters or by sensitive molecular techniques. Salinomycin, an antibacterial and coccidiodostatic ionophore, is reported (Cell 2009;138(4):645-59) to be >100-fold more potent against breast cancer cells with stem cell-like phenotype after mesenchymal transdifferentiation due to stable transfection with shRNA against CDH1 than against the parental cells. We evaluated whether salinomycin could also exhibit a similar activity against stem cell-like cells in multiple myeloma (MM). To establish a comparative reference for such potential activity, we first tested salinomycin (0-10 uM for up to 72hrs) against a panel of 15 MM cell lines and observed IC50 values <1 uM in 10/15 cell lines tested, including >80% reduction of tumor cell viability in 6/15 cell lines tested at 0.5 uM, i.e. levels lower than the IC50 values for in vitro activity of salinomycin against breast cancer cells with (HMLE-shCDH1, IC50 ∼1 uM) or without (HMLE-shControl, IC50 >>10 uM) stem cell-like features. CD138+ purified primary tumor cells from 3 MM patients responded to salinomycin with IC50 values (105, 332 and 750 nM, respectively) in the same range as MM cell lines. In vitro combinations with bortezomib, doxorubicin, melphalan, and dexamethasone showed overall no antagonism, while evidence of additive or even synergistic effect could be identified in certain dose ranges. Because MM cell lines and primary tumor cells responded concordantly to salinomycin and with higher sensitivity than breast cancer stem cell-like cells, we hypothesized that MM cells may in general be more responsive to salinomycin than other tumors. Since tumor-stromal interactions can increase the expression of transcriptional signatures of “stemness” in MM cells, we embarked on characterizing the anti-MM properties of salinomycin using compartment-specific bioluminescence imaging (CSBLI) assays. These showed that co-culture with stromal cells did not confer resistance to salinomycin in 5 MM cell lines (MM.1S, OCI-My5, KMS-11, KMS-18, NCI-H929) and in fact enhanced its activity against 4 of them. Side population (SP) cells, defined by their ability to efflux Hoechst stain, represent a stem cell-like population which was identified in MM cell lines and could represent the functional equivalent of the mesenchymally transdifferentiated breast cancer stem cell-like cells. We observed that salinomycin reduces the SP fraction of MM cell lines at doses >20 times lower than those required for in vitro effect against the bulk <<main population>> of the respective cell lines. Interestingly, the anti-SP effect of salinomycin was more pronounced in the presence of stroma, similarly to the CSBLI studies on the entire MM cell population and consistent with our prior observation that tumor-stroma interaction enhances transcriptional signatures of ≪stemness≫ in the tumor compartment. However, when we tested the in vivo anti-MM activity of salinomycin in an orthotopic model of i.v. injected Luc+ MM cells, no anti-MM activity (in terms of tumor burden decrease or overall survival prolongation) was observed at the maximum tolerated dose (1 mg/kg i.p. daily, which is consistent with most studies reported thus far in the literature). Ex vivo treatment of KMS-11 cells with salinomycin doses (100 nM for 72 hrs) selectively targeting SP cells was followed by s.c. injection of these cells or vehicle-treated controls in sublethallly irradiated SCID/NOD mice, but no statistically significant improvement in tumor burden or overall survival was observed. Our in vitro results indicate that salinomycin exhibits intriguing in vitro anti-MM activity, not only against SP cells but also against the bulk ≪main≫ MM cell population, even in the presence of stromal support. In contrast, the in vivo activity of salinomycin is compromised by side effects in the orthotopic model of MM lesions, while short term ex vivo exposure of tumor cells is conceivably insufficient to eradicate clonogenic cells and lead to appreciable delay in tumor growth in vivo. Our studies point to intriguing features as well as notable challenges that have to overcome before salinomycin or other more selective agents of this class can be safely tested in clinical trials in MM. Disclosures: McMillin: Axios Biosciences: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck &Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding.
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Hua, Jianyu, Lixin Zang, Huimin Zhao, Ting Liu, Ming Fan, Tong Chen, Zhengyu Cao, Ye Tian, and Zhiguo Zhang. "Studying the origin of fluorescence emissions of neodymium porphyrin based on the analysis of energy level structure." Journal of Porphyrins and Phthalocyanines 21, no. 10 (October 2017): 665–70. http://dx.doi.org/10.1142/s1088424617500651.
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This paper studies the origin of fluorescence emissions of metalloporphyrins. The absorption spectrum of neodymium-coordinated hematoporphyrin monomethyl ether (Nd-HMME) was found to have four Q bands, which is different from the accepted knowledge (two Q bands). The absorbance of Nd-HMME was comparable to the corresponding absorbance of HMME at wavelengths of 538 nm and 572 nm, but the absorbance of Nd-HMME at wavelengths of 502 nm and 622 nm was approximately 1/30 of that at 572 nm. The doping of Nd[Formula: see text] enhanced the symmetry of HMME, and led to changes in energy level properties. Moreover, Nd-HMME still exhibited two fluorescence peaks at 624 nm and 686 nm, similar to HMME, which can be explained by the observation of a weak absorption peak of Nd-HMME at 622 nm.
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Yee Ann, Lee, P. Ehkan, M. Y. Mashor, and S. M. Sharun. "FPGA-based architecture of hybrid multilayered perceptron neural network." Indonesian Journal of Electrical Engineering and Computer Science 14, no. 2 (May 1, 2019): 949. http://dx.doi.org/10.11591/ijeecs.v14.i2.pp949-956.
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<span lang="EN-MY">The HMLP is an ANN similar to the MLP, but with extra weighted connections that connect the input nodes directly to the output nodes. The architecture of the HMLP neural network for implementation on FPGA is proposed. The HMLP architecture is designed to be concurrent to demonstrate the parallel nature of the HMLP where each hidden or output node within the same hidden or output layer of the HMLP can calculate its output independently. The HMLP architecture is designed to be modular as well, such that if modification to a module is necessary, only the specific module need to be modified and all other modules can be retained. This modularity will be especially helpful when different activation function is to be swapped in to replace current activation function. All calculations in the HMLP are performed in floating-point arithmetic. The HMLP architecture is compiled, simulated and finally implemented on the Cyclone V FPGA of DE1-SoC board. The simulation outcome and FPGA outputs showed that the developed HMLP architecture is able to calculate correct output values for all test datasets.</span>
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Rolff, Hans C., Rikard B. Ambrus, Mohammed Belmouhand, Michael P. Achiam, Marianne Wegmann, Mette Siemsen, Steen C. Kofoed, and Lars B. Svendsen. "Robot-Assisted Hybrid Esophagectomy Is Associated with a Shorter Length of Stay Compared to Conventional Transthoracic Esophagectomy: A Retrospective Study." Minimally Invasive Surgery 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/6907896.
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Aim. To compare the peri- and postoperative data between a hybrid minimally invasive esophagectomy (HMIE) and the conventional Ivor Lewis esophagectomy. Methods. Retrospective comparison of perioperative characteristics, postoperative complications, and survival between HMIE and Ivor Lewis esophagectomy. Results. 216 patients were included, with 160 procedures performed with the conventional and 56 with the HMIE approach. Lower perioperative blood loss was found in the HMIE group (600 ml versus 200 ml, p<0.001). Also, a higher median number of lymph nodes were harvested in the HMIE group (median 28) than in the conventional group (median 23) (p=0.002). The median length of stay was longer in the conventional group compared to the HMIE group (11.5 days versus 10.0 days, p=0.03). Patients in the HMIE group experienced fewer grade 2 or higher complications than the conventional group (39% versus 57%, p=0.03). The rate of all pulmonary (51% versus 43%, p=0.32) and severe pulmonary complications (38% versus 18%, p = 0.23) was not statistically different between the groups. Conclusions. The HMIE was associated with lower intraoperative blood loss, a higher lymph node harvest, and a shorter hospital stay. However, the inborn limitations with the retrospective design stress a need for prospective randomized studies. Registration number is DRKS00013023.
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Grover, Sandeep, Aseem Mehra, Subho Chakrabarti, and Ajit Avasthi. "Association of Cognitive and Noncognitive Symptoms of Delirium: A Study from Consultation-liaison Psychiatry Set-up." Journal of Neurosciences in Rural Practice 07, S 01 (December 2016): S007—S012. http://dx.doi.org/10.4103/0976-3147.196440.
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ABSTRACT Aims: This study aims to evaluate the cognitive functions of patients with delirium using Hindi Mental Status Examination (HMSE), to study the correlation of cognitive functions assessed by HMSE with noncognitive symptoms as assessed using Delirium Rating Scale-Revised 1998 (DRS-R-98) and to study the association of cognitive functions assessed using HMSE and DRS-R98. Methods: A total of 76 consecutive patients fulfilling the diagnosis of delirium were evaluated on DRS-R-98, HMSE, and Short Informant Questionnaire on Cognitive Decline in the Elderly (retrospective IQCODE). Results: The mean DRS-R-98 score 33.9 (standard deviation [SD] - 7.2) and the mean DRS-R-98 severity score was 25.9 (SD - 7.2). The mean score on HMSE was 19.3 (7.98). There were significant correlations of all the domains of HMSE with DRS-R-98 total score, DRS-R-98 severity score, DRS-R-98 cognitive subscale score, DRS-R-98 noncognitive domain subscale score, and DRS severity score without attention score. When the association of each item of DRS-R-98 and HMSE was evaluated, except for the items of delusions, lability of affect and motor retardation, there were significant negative association between all the items of DRS-R-98 and HMSE, indicating that higher severity of cognitive symptoms as assessed on HMSE is associated with higher severity of all the cognitive symptoms and most of the noncognitive symptoms as assessed by DRS-R-98. Conclusion: The present study suggests that attention deficits in patients with delirium influence the severity of cognitive and noncognitive symptoms of delirium. Further, the present study suggests an increase in the severity of cognitive symptoms in other domains is also associated with an increase in the severity of noncognitive symptoms of delirium.
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Xu, Kequan, Clara Pérez-Ràfols, Amine Marchoud, María Cuartero, and Gastón A. Crespo. "Anodic Stripping Voltammetry with the Hanging Mercury Drop Electrode for Trace Metal Detection in Soil Samples." Chemosensors 9, no. 5 (May 13, 2021): 107. http://dx.doi.org/10.3390/chemosensors9050107.
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The widely spread use of the hanging mercury drop electrode (HMDE) for multi-ion analysis is primarily ascribed to the following reasons: (i) excellent reproducibility owing to the easy renewal of the electrode surface avoiding any hysteresis effect (i.e., a new identical drop is generated for each measurement to be accomplished); (ii) a wide cathodic potential window originating from the passive hydrogen evolution and solvent electrolysis; (iii) the ability to form amalgams with many redox-active metal ions; and (iv) the achievement of (sub)nanomolar limits of detection. On the other hand, the main controversy of the HMDE usage is the high toxicity level of mercury, which has motivated the scientific community to question whether the HMDE deserves to continue being used despite its unique capability for multi-metal detection. In this work, the simultaneous determination of Zn2+, Cd2+, Pb2+, and Cu2+ using the HMDE is investigated as a model system to evaluate the main features of the technique. The analytical benefits of the HMDE in terms of linear range of response, reproducibility, limit of detection, proximity to ideal redox behavior of metal ions and analysis time are herein demonstrated and compared to other electrodes proposed in the literature as less-toxic alternatives to the HMDE. The results have revealed that the HMDE is largely superior to other reported methods in several aspects and, moreover, it displays excellent accuracy when simultaneously analyzing Zn2+, Cd2+, Pb2+, and Cu2+ in such a complex matrix as digested soils. Yet, more efforts are required towards the definitive replacement of the HMDE in the electroanalysis field, despite the elegant approaches already reported in the literature.
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Jin, Weiwei, Yanxue Yin, Bo Zhang, Heng Mei, Huafang Wang, Tao Guo, Wei Shi, and Yu Hu. "A tissue factor-cascade-targeted nanoparticle forsite-directed inducing thrombosis." Journal of Biomaterials Applications 32, no. 3 (July 24, 2017): 342–48. http://dx.doi.org/10.1177/0885328217722740.
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Tissue factor is an upstream component of the cascade and a high-expressing factor under phathological conditions. In this study, a tissue factor cascade-targeted strategy for inducing local thrombosis was developed by combining ENP-HMME and photochemistry. In vitro study showed that protein EGFP-EGF1 conjugation to the nanoparticles could significantly contribute to the uptake of nanoparticles by tissue factor over-expressed brain capillary endothelial cells. Three-dimensional imaging and specklegram of brains in vivo showed that tissue factor cascade-targeted strategy successfully induced thrombosis of expected position. As shown by the in vivo multispectral fluorescent imaging, when ENP-HMME was combined with photochemistry, higher accumulation in the infarction hemisphere was observed, which might suggest that the photochemistry inducing tissue factor cascade recruited more ENP-HMME than HMME-loaded nanoparticles (NP-HMME). The data indicated the tissue factor cascade-targeted strategy has potential to induce local thrombosis, and might be applied in the treatment of a variety of hypervascular diseases.
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Benatti, Hector R., Hermes R. Luz, Daniel M. Lima, Vinicius D. Gonçalves, Francisco B. Costa, Vanessa N. Ramos, Daniel M. Aguiar, et al. "Morphometric Patterns and Blood Biochemistry of Capybaras (Hydrochoerus hydrochaeris) from Human-Modified Landscapes and Natural Landscapes in Brazil." Veterinary Sciences 8, no. 8 (August 13, 2021): 165. http://dx.doi.org/10.3390/vetsci8080165.
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The capybara, Hydrochoerus hydrochaeris, is the largest extant rodent of the world. To better understand the correlation between size and body mass, and biochemical parameters of capybaras from areas with different degrees of anthropization (i.e., different food supplies), we sampled free-ranging capybaras from areas of natural landscapes (NLs) and human-modified landscapes (HMLs) in Brazil. Analyses of biometrical and biochemical parameters of capybaras showed that animals from HMLs were heavier (higher body mass) than those from NL, a condition possibly related to fat deposit rather than body length, as indicated by Body Condition Index (BCI) analyses. Biochemical parameters indicated higher serum levels of albumin, creatine kinase, cholesterol, fructosamine and total protein among capybaras from HMLs than from NLs; however, when all adult capybaras were analyzed together only cholesterol and triglycerides were positively correlated with body mass. We propose that the biochemical profile differences between HMLs and NLs are related to the obesity condition of capybaras among HMLs. Considering that heavier animals might live longer and reproduce more often, our results could have important implications in the population dynamics of capybaras among HMLs, where this rodent species is frequently represented by overgrowth populations that generate several levels of conflicts with human beings.
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Zhong, Shan, Quan Liu, and QiMing Fu. "Efficient Actor-Critic Algorithm with Hierarchical Model Learning and Planning." Computational Intelligence and Neuroscience 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/4824072.
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To improve the convergence rate and the sample efficiency, two efficient learning methods AC-HMLP and RAC-HMLP (AC-HMLP withl2-regularization) are proposed by combining actor-critic algorithm with hierarchical model learning and planning. The hierarchical models consisting of the local and the global models, which are learned at the same time during learning of the value function and the policy, are approximated by local linear regression (LLR) and linear function approximation (LFA), respectively. Both the local model and the global model are applied to generate samples for planning; the former is used only if the state-prediction error does not surpass the threshold at each time step, while the latter is utilized at the end of each episode. The purpose of taking both models is to improve the sample efficiency and accelerate the convergence rate of the whole algorithm through fully utilizing the local and global information. Experimentally, AC-HMLP and RAC-HMLP are compared with three representative algorithms on two Reinforcement Learning (RL) benchmark problems. The results demonstrate that they perform best in terms of convergence rate and sample efficiency.
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Damirov, Fuad, Karen Büsing, Gökce Yavuz, Rudolf Hatz, Farkhad Manapov, Julia Michels, Peter Hohenberger, and Eric Roessner. "Preoperative Hilar and Mediastinal Lymph Node Staging in Patients with Suspected or Diagnosed Lung Cancer: Accuracy of 18F-FDG-PET/CT:A Retrospective Cohort Study of 138 Patients." Diagnostics 13, no. 3 (January 22, 2023): 403. http://dx.doi.org/10.3390/diagnostics13030403.
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The aim of this study was to evaluate the diagnostic accuracy of integrated 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG-PET/CT) in hilar and mediastinal lymph node (HMLN) staging of suspected or proven lung cancer, and to investigate potential risk factors for false negative and false positive HMLN metastases. We retrospectively analyzed 162 consecutive patients with suspected or pathologically proven non-small cell lung cancer (NSCLC). The receiver operating characteristic (ROC) curve was generated to determine the diagnostic efficacy of 18F-FDG-PET/CT. Univariate and multivariate analyses were conducted to detect risk factors of false positives and false negatives. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of integrated 18F-FDG-PET/CT in detecting HMLN metastases were 59.1% (26/44), 69.1% (65/94), 47.3% (26/55), 78.3% (65/83), and 65.9% (91/138), respectively. The ROC curve showed an area under the curve (AUC) of 0.625 (95%-CI 0.468–0.782). The incidence of false negative and false positive HMLN metastases was 21.7% (18/83) and 52.7% (29/55), respectively. Our data shows that integrated 18F-FDG-PET/CT staging provides lower specificity and sensitivity. This confirms the ESTS guideline on lymph node staging for PET-positive HMLN. Yet it advocates more invasive staging even for PET-negative HMLN.
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Shikani, Alan H., Elamin M. Elamin, and Andrew C. Miller. "The Shikani HME: A New Tracheostomy Heat and Moisture Exchanger." Journal of Speech, Language, and Hearing Research 63, no. 9 (September 15, 2020): 2921–29. http://dx.doi.org/10.1044/2020_jslhr-19-00107.
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Purpose Tracheostomy patients face many adversities including loss of phonation and essential airway functions including air filtering, warming, and humidification. Heat and moisture exchangers (HMEs) facilitate humidification and filtering of inspired air. The Shikani HME (S-HME) is a novel turbulent airflow HME that may be used in-line with the Shikani Speaking Valve (SSV), allowing for uniquely preserved phonation during humidification. The aims of this study were to (a) compare the airflow resistance ( R airflow ) and humidification efficiency of the S-HME and the Mallinckrodt Tracheolife II tracheostomy HME (M-HME) when dry (time zero) and wet (after 24 hr) and (b) determine if in-line application of the S-HME with a tracheostomy speaking valve significantly increases R airflow over a tracheostomy speaking valve alone (whether SSV or Passy Muir Valve [PMV]). Method A prospective observational ex vivo study was conducted using a pneumotachometer lung simulation unit to measure airflow ( Q ) amplitude and R airflow , as indicated by a pressure drop ( P Drop ) across the device (S-HME, M-HME, SSV + S-HME, and PMV). Additionally, P Drop was studied for the S-HME and M-HME when dry at time zero (T 0 ) and after 24 hr of moisture testing (T 24 ) at Q of 0.5, 1, and 1.5 L/s. Results R airflow was significantly less for the S-HME than M-HME (T 0 and T 24 ). R airflow of the SSV + S-HME in series did not significant increase R airflow over the SSV or PMV alone. Moisture loss efficiency trended toward greater efficiency for the S-HME; however, the difference was not statistically significant. Conclusions The turbulent flow S-HME provides heat and moisture exchange with similar or greater efficacy than the widely used laminar airflow M-HME, but with significantly lower resistance. The S-HME also allows the innovative advantage of in-line use with the SSV, hence allowing concurrent humidification and phonation during application, without having to manipulate either device.
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Fong, Wai Mun. "Value without HML." Journal of Investing 26, no. 4 (November 27, 2017): 105–21. http://dx.doi.org/10.3905/joi.2017.26.4.105.
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Kuvendjiska, Jasmina, Goran Marjanovic, Torben Glatz, Birte Kulemann, and Jens Hoeppner. "Hybrid Minimally Invasive Esophagectomy–Surgical Technique and Results." Journal of Clinical Medicine 8, no. 7 (July 5, 2019): 978. http://dx.doi.org/10.3390/jcm8070978.
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Background: Hybrid minimally invasive esophagectomy (HMIE) has been proven to be superior when compared with open esophagectomy, with a significant reduction of postoperative morbidity. In HMIE, the laparotomy is replaced by a minimally invasive laparoscopic approach. The radical mediastinal resection plus reconstruction is performed by a thoracic approach through a muscle-sparing thoracotomy. In this instructional article, we describe the surgical technique of HMIE in detail in order to facilitate possible adoption of the procedure by other surgeons. In addition, we give the monocentric results of our own practice. Methods: Between 2013 and 2018, HMIE was performed in 157 patients. The morbidity and mortality data of the procedure is shown in a retrospective monocentric analysis. Results: Overall, 54% of patients had at least one perioperative complication. Anastomotic leak was evident in 1.9%, and a single patient had focal conduit necrosis of the gastric pull-up. Postoperative pulmonary morbidity was 31%. Pneumonia was found in 17%. The 90 day mortality was 2.5%. Wound infection rate was 3%, and delayed gastric emptying occurred in 17% of patients. In follow up, 12.7% presented with diaphragmatic herniation of the bowel, requiring laparoscopic hernia reduction and hiatal reconstruction and colopexy several months after surgery. Conclusion: HMIE is a highly reliable technique, not only for the resection part but especially in terms of safety in reconstruction and anastomosis. For esophageal surgeons with experience in minimally invasive anti-reflux procedures and obesity surgery, HMIE is easy and fast to learn and adopt.
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Zhuang, Deshu, Zongshan Ji, Liangjia Bi, Xiaochun Wang, Qi Zhou, and Wenwu Cao. "Low-Intensity Ultrasound Combined with Hematoporphyrin Monomethyl Ether in the Treatment of Experimental Periodontitis in Rats." BioMed Research International 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/7156716.
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Objectives. This study aims to evaluate the efficacy of hematoporphyrin monomethyl ether- (HMME-) mediated sonodynamic therapy (SDT) on experimental periodontal disease in rats. Methods. Periodontal disease was induced by submerging ligatures at the first maxillary molar subgingival region in forty-eight male SD rats. After 30 days, the ligatures were removed. The rats were randomly allocated into four groups; the experimental SDT group was treated through hypodermic injection of 40 μg/mL HMME and 3 W/cm2 low-intensity ultrasound irradiation (1 MHz, 600 s). Those in control groups received 40 μg/mL HMME alone (control 1 group) or 3 W/cm2 ultrasound irradiation alone (control 2 group) or were subjected to neither HMME nor ultrasound (control 3 group). After 10 days of treatment, all rats were euthanized, the maxilla was obtained for histological examination, and the alveolar bone level was evaluated by histometric analysis. Results. The control groups showed more bone loss (P<0.05) after 10 days of treatment than the SDT group. There is no significant difference among the control groups (P>0.05). Conclusions. HMME mediated SDT was an effective therapy of experimental periodontal tissue in rats.
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Wang, Ping, Luwei Zhang, Zhenxi Zhang, Sijia Wang, and Cuiping Yao. "Influence of Parameters on Photodynamic Therapy of Au@TiO2–HMME Core-Shell Nanostructures." Nanomaterials 12, no. 8 (April 15, 2022): 1358. http://dx.doi.org/10.3390/nano12081358.
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Photodynamic therapy (PDT) is a promising tumor therapy and has been proven to be an effective, safe and minimally invasive technique. Hematoporphyrin monomethyl ether (HMME) mediated PDT has been used in clinical treatment of port wine stain (PWS) due to its single component, high yield of singlet oxygen and short light-sensitive period. However, as an amphiphilic photosensitizer, HMME is easy to aggregate due to the presence of a hydrophobic group, which undesirably reduced its generation of singlet oxygen and bioavailability. In this study, we synthesized the stable conjugate of Au@TiO2 core-shell nanostructure with HMME, and the influence of different factors on PTD efficiency were studied. The results showed that the nanostructure had higher PTD efficiency for KB cells than that of HMME. The irradiation wavelength, gold nanoparticle shape and the shell thickness are all important factors for KB cell PDT.
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Ruprecht, Klemens, Humberto Ferreira, Aline Flockerzi, Silke Wahl, Marlies Sauter, Jens Mayer, and Nikolaus Mueller-Lantzsch. "Human Endogenous Retrovirus Family HERV-K(HML-2) RNA Transcripts Are Selectively Packaged into Retroviral Particles Produced by the Human Germ Cell Tumor Line Tera-1 and Originate Mainly from a Provirus on Chromosome 22q11.21." Journal of Virology 82, no. 20 (August 6, 2008): 10008–16. http://dx.doi.org/10.1128/jvi.01016-08.
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ABSTRACT The human germ cell tumor line Tera-1 produces retroviral particles which are encoded by the human endogenous retrovirus family HERV-K(HML-2). We show here, by quantitative reverse transcriptase PCR, that HML-2 gag and env RNA transcripts are selectively packaged into Tera-1 retroviral particles, whereas RNAs from cellular housekeeping genes and from other HERV families (HERV-H and HERV-W) are nonselectively copackaged. Assignment of cloned HML-2 gag and env cDNAs from Tera-1 retroviral particles to individual HML-2 loci in the human genome demonstrated that HML-2 RNA transcripts packaged into Tera-1 retroviral particles originate almost exclusively from an HML-2 provirus on chromosome 22q11.21. Based on relative cloning frequencies, this provirus was the most active among a total of eight transcribed HML-2 loci identified in Tera-1 cells. These data suggest that at least one HML-2 element, that is, the HML-2 provirus on 22q11.21, has retained the capacity for packaging RNA into HML-2-encoded retroviral particles. Given its elevated transcriptional activity and the presence of a full-length Gag open reading frame, the 22q11.21 HML-2 provirus may also significantly contribute to Gag protein and thus particle production in Tera-1 cells. Our findings provide important clues to the generation and biological properties of HML-2-encoded particles. In addition, copackaging of non-HML-2 HERV transcripts in HML-2-encoded particles should inform the debate about endogenous retroviral particles putatively encoded by non-HML-2 HERV families that have previously been described for other human diseases, such as multiple sclerosis.
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Magioli, Marcelo, Marcelo Zacharias Moreira, Renata Cristina Batista Fonseca, Milton Cezar Ribeiro, Márcia Gonçalves Rodrigues, and Katia Maria Paschoaletto Micchi de Ferraz. "Human-modified landscapes alter mammal resource and habitat use and trophic structure." Proceedings of the National Academy of Sciences 116, no. 37 (August 26, 2019): 18466–72. http://dx.doi.org/10.1073/pnas.1904384116.
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The broad negative consequences of habitat degradation on biodiversity have been studied, but the complex effects of natural–agricultural landscape matrices remain poorly understood. Here we used stable carbon and nitrogen isotopes to detect changes in mammal resource and habitat use and trophic structure between preserved areas and human-modified landscapes (HMLs) in a biodiversity hot spot in South America. We classified mammals into trophic guilds and compared resource use (in terms of C3- and C4-derived carbon), isotopic niches, and trophic structure across the 2 systems. In HMLs, approximately one-third of individuals fed exclusively on items from the agricultural matrix (C4), while in preserved areas, ∼68% depended on forest remnant resources (C3). Herbivores, omnivores, and carnivores were the guilds that most incorporated C4carbon in HMLs. Frugivores maintained the same resource use between systems (C3resources), while insectivores showed no significant difference. All guilds in HMLs except insectivores presented larger isotopic niches than those in preserved areas. We observed a complex trophic structure in preserved areas, with increasing δ15N values from herbivores to insectivores and carnivores, differing from that in HMLs. This difference is partially explained by species loss and turnover and mainly by the behavioral plasticity of resilient species that use nitrogen-enriched food items. We concluded that the landscape cannot be seen as a habitat/nonhabitat dichotomy because the agricultural landscape matrix in HMLs provides mammal habitat and opportunities for food acquisition. Thus, favorable management of the agricultural matrix and slowing the conversion of forests to agriculture are important for conservation in this region.
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Nam, Jain, Kyeong Jin Kim, Geonhee Park, Byeong Goo Kim, Gwi-Hwa Jeong, Jong-eun Jeon, Byung Serk Hurh, and Ji Yeon Kim. "Anti-Inflammatory Properties of Mineral-Balanced Deep Sea Water in In-Vitro and In-Vivo Models of Inflamed Intestinal Epithelium." Applied Sciences 10, no. 15 (July 28, 2020): 5183. http://dx.doi.org/10.3390/app10155183.
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This study aimed to determine the effect of deep-sea water (DSW)-derived mineral waters on intestinal health, using a cell model and a dextran sulfate sodium (DSS)-induced enteritis mouse model. DSW was desalted and minerals were added to generate mineral waters that were classified as trace mineral (TM), high magnesium (HM), high magnesium low salt (HMLS), and high magnesium high calcium (HMHC), using a tabletop electrodialysis device. Caco-2 cells cocultured with Raw264.7 cells were either pre-treated or not with the four water groups, and inflammation was induced by treatment with lipopolysaccharide (LPS). Compared to LPS-treated Caco-2 cells, HMLS-cotreated cells maintained high transepithelial electrical resistance, similar to control cells. FITC-dextran permeability was lower in HMLS-treated than in other cells. In vivo, in comparison to DSS-treated mice, colon shortening was inhibited, and disease activity and colon injury were suppressed in HMLS-cotreated mice. RNA-seq of colonic tissues revealed that inflammatory gene expression was similar among the control and HMLS mice, and DSS-induced expression of inflammation-related genes such as TNF-α and NOS2 and inflammatory chemokine genes was suppressed. Our findings suggest that DSW-derived mineral water intake can help reduce colitis symptoms, and the effects may be partially regulated by magnesium and other minerals.
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Lin, Wenshu, Weiwei Fan, Haoran Liu, Yongsheng Xu, and Jinzhuo Wu. "Classification of Handheld Laser Scanning Tree Point Cloud Based on Different KNN Algorithms and Random Forest Algorithm." Forests 12, no. 3 (March 3, 2021): 292. http://dx.doi.org/10.3390/f12030292.
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Handheld mobile laser scanning (HMLS) can quickly acquire point cloud data, and has the potential to conduct forest inventory at the plot scale. Considering the problems associated with HMLS data such as large discreteness and difficulty in classification, different classification models were compared in order to realize efficient separation of stem, branch and leaf points from HMLS data. First, the HMLS point cloud was normalized and ground points were removed, then the neighboring points were identified according to three KNN algorithms and eight geometric features were constructed. On this basis, the random forest classifier was used to calculate feature importance and perform dataset training. Finally, the classification accuracy of different KNN algorithms-based models was evaluated. Results showed that the training sample classification accuracy based on the adaptive radius KNN algorithm was the highest (0.9659) among the three KNN algorithms, but its feature calculation time was also longer; The validation accuracy of two test sets was 0.9596 and 0.9201, respectively, which is acceptable, and the misclassification mainly occurred in the branch junction of the canopy. Therefore, the optimal classification model can effectively achieve the classification of stem, branch and leaf points from HMLS point cloud under the premise of comprehensive training.
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Suga, Yuki, Tetsuya Ogata, and Shigeki Sugano. "Human-Adaptive Robot Interaction Using Interactive EC with Human-Machine Hybrid Evaluation." Journal of Robotics and Mechatronics 20, no. 4 (August 20, 2008): 610–20. http://dx.doi.org/10.20965/jrm.2008.p0610.
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Using interactive evolutionary computation (IEC), we created human-robot interaction system that maintains user interest over time. Although IEC enables users to design systems reflecting subjective preferences, it forces them to evaluate a large number of individuals. The refined IEC techniques, we propose in this regard, human-machine hybrid evaluation (HMHE), lets users manually evaluate only representative genes, after which HMHE automatically estimates the fitness of other genes, thereby increasing a population without increasing user evaluation process. Experimental results showed that preferences easily change in interaction. We confirmed that HMHE maintains high diversity, while maintaining user interest.
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Mustika, Martina Dwi, and Chris J. Jackson. "How rationality predicts individual perception of safety climate: An application of the hybrid model of learning in personality." Psikohumaniora: Jurnal Penelitian Psikologi 5, no. 1 (April 30, 2020): 45. http://dx.doi.org/10.21580/pjpp.v5i1.5274.
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<p class="APANormalAbstract">Jackson’s (2008) Hybrid Model of Learning in Personality (HMLP) is designed to measure the effect of biological, socio-cognitive, and experiential processes of personality and learning mechanisms on developing rationality and directing functional or dysfunctional behaviors of employees. We use HMLP to determine if rational thinking predicts individual perception of safety climate. The results found that the proposed indirect paths of learning mechanisms significantly predict the individual perception of a safety climate through rationality. The goodness-of-fit demonstrated that the model provided a satisfactory fit: c2 = 13.200, p = 0.067; RMS = 0.000; RMSEA = 0.063; GFI = 0.981; AGFI = 0.943; and CFI = 0.988. As a result, we identify the importance of rationality in predicting individual safety climate and once again confirm the usefulness of HMLP in predicting useful workplace outcomes. The HMLP offers valuable insights into the influence of rationality in predicting individual perception of safety climate, as well as the underlying process of developing rationality.</p>
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KIM, Hyunggee, James FARRIS, Shelly A. CHRISTMAN, Byung-Whi KONG, Linda K. FOSTER, Scott M. O'GRADY, and Douglas N. FOSTER. "Events in the immortalizing process of primary human mammary epithelial cells by the catalytic subunit of human telomerase." Biochemical Journal 365, no. 3 (August 1, 2002): 765–72. http://dx.doi.org/10.1042/bj20011848.
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The in vitro immortalization of primary human mammary epithelial (HME) cells solely by the exogenous introduction of the catalytic subunit of human telomerase (hTERT) has been achieved. Early passage hTERT-transfected HME (T-HME) cells continuously decreased the length and density of telomeres even in the presence of telomerase activity, with a significant number of cells staining positive for senescence-associated β-galactosidase (SA-β-gal). Subsequently, with the increase in cell passages, the copy number of the exogenously transfected hTERT gene and the percentage of SA-β-gal positive cells were found to decrease. Eventually, a single copy of the exogenous hTERT gene was observed in the relatively later passage T-HME cells in which telomere length was elongated and stabilized without obvious activation of endogenous hTERT and c-Myc expression. In T-HME cells, the expression of two p53 regulated genes p21WAF and HDM2 increased (as in primary senescent HME cells), and was found to be further elevated as the function of p53 was activated by treatment with DNA-damaging agents. p16INK4a was shown to be significantly higher in the primary senescent HME and the early passage T-HME cells when compared with the primary presenescent HME cells, with a dramatic repression of p16INK4a observed in the later passage T-HME cells. In addition, the expression of E2F1 and its transcription factor activity were found to be significantly higher in the later passage T-HME cells when compared with the earlier passage T-HME cells. Together, our results indicate that in vitro immortalization in HME cells may require the activation of the function of telomerase and other genetic alterations such as the spontaneous loss of p16INK4a expression.
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García-Calvo, Tomás, José Carlos Ponce-Bordón, Eduard Pons, Roberto López del Campo, Ricardo Resta, and Javier Raya-González. "High metabolic load distance in professional soccer according to competitive level and playing positions." PeerJ 10 (September 20, 2022): e13318. http://dx.doi.org/10.7717/peerj.13318.
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Background High metabolic load distance provides global information about the soccer players’ total high-intensity activities. Thus, this study aimed to examine the Spanish professional soccer players’ high metabolic load distance profile, comparing competitive level and playing positions. Methods A total of 18,131 individual match observations were collected from outfield players competing during the 2018/2019 and 2019/20 seasons in the First and Second Spanish Professional Soccer Leagues (LaLiga™). High Metabolic Load Distance (HMLD; distance covered with a power consumption above 25.5 W·kg−1 and accelerations or decelerations (e.g., accelerating from 2 to 4 m·s−2 for 1 s) were included), and HMLD per minute (HMLDmin) were analyzed by the ChryonHego® video-tracking system. Players were classified according to their playing position as follows: Central Backs (CB), Full Backs (FB), Center Midfields (CM), Wide Midfields (WM), and Forwards (FW). Results No differences between competitive levels were found in any variable when all players were analyzed conjointly except for HMLDmin overall and during the second half. However, when playing positions were considered, differences between competitive levels were observed in all positions, mainly in HMLD and HMLD during the first-half variables. In addition, several differences between playing positions were observed, with CB presenting the lowest values in all variables compared to their counterparts in both competitive levels, whereas CM in First Division and WM in Second Division showed the highest values in the HMLD variables. Discussion The findings are of interest to analyze the HMLD in professional soccer players, enabling the adaptation and individualization of training in this population according to the competitive level and specific playing position of each player.
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Gardiner, Elliroma, and Chris J. Jackson. "Personality and learning processes underlying maverickism." Journal of Managerial Psychology 30, no. 6 (August 10, 2015): 726–40. http://dx.doi.org/10.1108/jmp-07-2012-0230.
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Purpose – Maverickism is the tendency of an individual to be socially competent, creative, goal focussed, risk-taking and disruptive. Previous research with the five-factor model (FFM) shows that individuals high in maverickism exhibit both functional and dysfunctional tendencies. The purpose of this paper is to compare and contrast the descriptive FFM with the process-oriented hybrid model of learning in personality (HMLP), in the prediction of maverickism. Design/methodology/approach – Employing a cross-sectional design with 490 full-time workers the authors use the NEO-International Personality Item Pool and the Learning Styles Profiler to examine differences in the FFM and HMLP in the prediction of maverickism. Findings – Results with the FFM, identify extraversion, openness and (low) agreeableness as significant predictors of maverickism. All factors of the HMLP (except conscientious learning) significantly predict maverickism. Hierarchal regression analysis shows that the HMLP accounts for an additional 21 percent of variance in maverickism over and above that of the FFM. Research limitations/implications – The authors have tested and built theory by identifying not only what predicts maverickism, but also how the learning processes of the HMLP interrelate to predict maverickism. Practical implications – Managers interested in developing the maverick potential of their employees will find this study useful because it identifies what to look for in maverick workers. Social implications – Individuals high in maverickism have the potential for radical innovation. Understanding how to identify and develop these individuals may lead to larger societal benefits. Originality/value – The authors are the first to use the HMLP to test maverickism. The research highlights the importance of both personality and learning processes in maverickism.
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Lavie, Laurence, Milena Kitova, Esther Maldener, Eckart Meese, and Jens Mayer. "CpG Methylation Directly Regulates Transcriptional Activity of the Human Endogenous Retrovirus Family HERV-K(HML-2)." Journal of Virology 79, no. 2 (January 15, 2005): 876–83. http://dx.doi.org/10.1128/jvi.79.2.876-883.2005.
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ABSTRACT A significant proportion of the human genome consists of stably inherited retroviral sequences. Most human endogenous retroviruses (HERVs) became defective over time. The HERV-K(HML-2) family is exceptional because of its coding capacity and the possible involvement in germ cell tumor (GCT) development. HERV-K(HML-2) transcription is strongly upregulated in GCTs. However, regulation of HERV-K(HML-2) transcription remains poorly understood. We investigated in detail the role of CpG methylation on the transcriptional activity of HERV-K(HML-2) long terminal repeats (LTRs). We find that CpG sites in various HERV-K(HML-2) proviral 5′ LTRs are methylated at different levels in the cell line Tera-1. Methylation levels correlate with previously observed transcriptional activities of these proviruses. CpG-mediated silencing of HERV-K(HML-2) LTRs is further corroborated by transcriptional inactivity of in vitro-methylated 5′ LTR reporter plasmids. However, CpG methylation levels do not solely regulate HERV-K(HML-2) 5′ LTR activity, as evidenced by different LTR activities in the cell line T47D. A significant number of mutated CpG sites in evolutionary old HERV-K(HML-2) 5′ LTRs suggests that CpG methylation had already silenced HERV-K(HML-2) proviruses millions of years ago. Direct silencing of HERV-K(HML-2) expression by CpG methylation enlightens upregulated HERV-K(HML-2) expression in usually hypomethylated GCT tissue.
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Dunaj, Ľubomír. "Spoločenská „hmla“ ako večný ľudský údel?" Philosophica Critica 7, no. 2 (December 15, 2021): 74–88. http://dx.doi.org/10.17846/pc.2021.7.2.74-88.
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Morozov, Vladimir A., and Alexey V. Morozov. "A Comprehensive Analysis of Human Endogenous Retroviruses HERV-K (HML.2) from Teratocarcinoma Cell Lines and Detection of Viral Cargo in Microvesicles." International Journal of Molecular Sciences 22, no. 22 (November 17, 2021): 12398. http://dx.doi.org/10.3390/ijms222212398.
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About 8% of our genome is composed of sequences from Human Endogenous Retroviruses (HERVs). The HERV-K (HML.2) family, here abbreviated HML.2, is able to produce virus particles that were detected in cell lines, malignant tumors and in autoimmune diseases. Parameters and properties of HML.2 released from teratocarcinoma cell lines GH and Tera-1 were investigated in detail. In most experiments, analyzed viruses were purified by density gradient centrifugation. HML.2 structural proteins, reverse transcriptase (RT) activity, viral RNA (vRNA) and particle morphology were analyzed. The HML.2 markers were predominantly detected in fractions with a buoyant density of 1.16 g/cm3. Deglycosylation of TM revealed truncated forms of transmembrane (TM) protein. Free virions and extracellular vesicles (presumably microvesicles—MVs) with HML.2 elements, including budding intermediates, were detected by electron microscopy. Viral elements and assembled virions captured and exported by MVs can boost specific immune responses and trigger immunomodulation in recipient cells. Sequencing of cDNA clones demonstrated exclusive presence of HERV-K108 env in HML.2 from Tera-1 cells. Not counting two recombinant variants, four known env sequences were found in HML.2 from GH cells. Obtained results shed light on parameters and morphology of HML.2. A possible mechanism of HML.2-induced diseases is discussed.
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Du, Xuqin, Jie Liu, Yiran Wang, Mulan Jin, and Qiao Ye. "Cobalt-related interstitial lung disease or hard metal lung disease: A case series of Chinese workers." Toxicology and Industrial Health 37, no. 5 (May 2021): 280–88. http://dx.doi.org/10.1177/07482337211000989.
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Hard metal lung disease (HMLD) is rarely diagnosed and is caused by the occupational inhalation of hard metal dust, mainly cobalt. The diagnosis of HMLD is based on a thorough occupational dust exposure combined with clinical–radiological–histological findings. We present a series of four Chinese workers who had occupational exposure to cobalt acid lithium or cobalt and tungsten dust. Four patients all complained of intermittent cough, chest tightness, or shortness of breath on exertion. High-resolution computed tomography scans presented bilateral ground-glass attenuation, consolidations, and/or reticular opacities with diffuse small nodules. Histologic findings showed that interstitial inflammation and fibrotic lesions distributed peribronchioles. The infiltrations by macrophages as well as visible multinucleated giant cells indicated giant cell interstitial pneumonia (GIP). Cobalt was detectable in the lung tissues of two patients measured by inductively-coupled plasma mass spectrometry. The first patient was diagnosed with cobalt-related interstitial lung disease (ILD), while the others were HMLD. GIP is the classic pathology of cobalt-related ILD or HMLD. One of the patients showed spontaneous remission after the cessation of exposure, while the other three recovered within 6–32 weeks after avoiding occupational exposure and using corticosteroids. At follow-up, all four patients showed no recurrence. A multidisciplinary diagnostic panel including occupational cobalt exposure evaluation is beneficial to recognize cobalt-related ILD or HMLD and to indicate the necessity of prevention.
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Kauppila, Joonas H., Helen Rosenlund, Fredrik Klevebro, Asif Johar, Poorna Anandavadivelan, Kalle Mälberg, and Pernilla Lagergren. "Minimally invasive surgical techniques for oesophageal cancer and nutritional recovery: a prospective population-based cohort study." BMJ Open 12, no. 9 (September 2022): e058763. http://dx.doi.org/10.1136/bmjopen-2021-058763.
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ObjectivesTo explore whether the minimally invasive oesophagectomy (MIE) or hybrid minimally invasive oesophagectomy (HMIE) are associated with better nutritional status and less weight loss 1 year after surgery, compared with open oesophagectomy (OE).DesignProspective cohort study.SettingAll patients undergoing oesophagectomy for cancer in Sweden during 2013–2018.ParticipantsA total of 424 patients alive at 1 year after surgery were eligible, and 281 completed the 1-year assessment. Of these, 239 had complete clinical data and were included in the analysis.Primary and secondary outcome measuresThe primary outcome was nutritional status at 1 year after surgery, assessed using the abbreviated Patient-Generated Subjective Global Assessment questionnaire. The secondary outcomes included postoperative weight loss at 6 months and 1 year after surgery.ResultsOf the included patients, 78 underwent MIE, 74 HMIE while 87 patients underwent OE. The MIE group had the highest prevalence of malnutrition (42% vs 22% after HMIE vs 25% after OE), reduced food intake (63% vs 45% after HMIE vs 39% after OE), symptoms reducing food intake (60% vs 45% after HMIE vs 60% after OE) and abnormal activities/function (45% vs 32% after HMIE vs 43% after OE). After adjustment for confounders, MIE was associated with a statistically significant increased risk of reduced food intake 1 year after surgery (OR 2.87, 95% CI 1.47 to 5.61), compared with OE. Other outcomes were not statistically significantly different between the groups. No statistically significant associations were observed between surgical techniques and weight loss up to 1 year after surgery.ConclusionsMIE was statistically significantly associated with reduced food intake 1 year after surgery. However, no differences were observed in weight loss between the surgical techniques. Further studies on nutritional impact of surgical techniques in oesophageal cancer are needed.
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Ali, Muhammad, Ghulam Hafeez, Ajmal Farooq, Zeeshan Shafiq, Faheem Ali, Muhammad Usman, and Lucian Mihet-Popa. "A Novel Control Approach to Hybrid Multilevel Inverter for High-Power Applications." Energies 14, no. 15 (July 28, 2021): 4563. http://dx.doi.org/10.3390/en14154563.
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This paper proposes a hybrid control scheme for a newly devised hybrid multilevel inverter (HMLI) topology. The circuit configuration of HMLI is comprised of a cascaded converter module (CCM), connected in series with an H-bridge converter. Initially, a finite set model predictive control (FS-MPC) is adopted as a control scheme, and theoretical analysis is carried out in MATLAB/Simulink. Later, in the real-time implementation of the HMLI topology, a hybrid control scheme which is a variant of the FS-MPC method has been proposed. The proposed control method is computationally efficient and therefore has been employed to the HMLI topology to mitigate the high-frequency switching limitation of the conventional MPC. Moreover, a comparative analysis is carried to illustrate the advantages of the proposed work that includes low switching losses, higher efficiency, and improved total harmonic distortion (THD) in output current. The inverter topology and stability of the proposed control method have been validated through simulation results in MATLAB/Simulink environment. Experimental results via low-voltage laboratory prototype have been added and compared to realize the study in practice.
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Bressan, Debra A., Julio Vazquez, and James E. Haber. "Mating type–dependent constraints on the mobility of the left arm of yeast chromosome III." Journal of Cell Biology 164, no. 3 (January 26, 2004): 361–71. http://dx.doi.org/10.1083/jcb.200311063.
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Mating-type gene (MAT) switching in budding yeast exhibits donor preference. MATa preferentially recombines with HML near the left telomere of chromosome III, whereas MATα prefers HMR near the right telomere. Donor preference is controlled by the recombination enhancer (RE) located proximal to HML. To test if HML is constrained in pairing with MATα, we examined live-cell mobility of LacI-GFP–bound lactose operator (lacO) arrays inserted at different chromosomal sites. Without induction of recombination, lacO sequences adjacent to HML are strongly constrained in both MATα and RE-deleted MATa strains, compared with MATa. In contrast, chromosome movement at HMR or near a telomere of chromosome V is mating-type independent. HML is more constrained in MATa Δre and less constrained in MATa RE+ compared with other sites. Although HML and MATa are not prealigned before inducing recombination, the three-dimensional configuration of MAT, HML, and HMR is mating-type dependent. These data suggest there is constitutive tethering of HML, which is relieved in MATa cells through the action of RE.
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Doucet-O'Hare, Tara, Jared Rosenblum, Brianna DiSanza, Catherine DeMarino, Abigail Atkinson, Nasir Malik, Joe Steiner, Harish Pant, Avindra Nath, and Zhengping Zhuang. "CSIG-24. TARGETED INHIBITION OF CDK5-MEDIATED REGULATION OF HUMAN ENDOGENOUS RETROVIRUS K (HML-2) ENVELOPE PROTEIN IN ATYPICAL TERATOID RHABDOID TUMOR." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi38. http://dx.doi.org/10.1093/neuonc/noab196.150.
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Abstract Atypical teratoid rhabdoid tumor (ATRT) is a pediatric brain tumor with a high mortality rate characterized by mutations in/ deletions of SWI/SNF matrix-associated actin-dependent regulator of chromatin sub-family B member 1 (SMARCB1). We previously showed that loss of SMARCB1 causes up-regulation and release of HML-2 subfamily of human endogenous retrovirus K envelope protein (HML-2 ENV), resulting in maintenance of pluripotency. Here, we investigated intracellular trafficking and release of HML-2 ENV. Further, we demonstrate two potential therapeutic strategies to decrease intracellular HML-2 ENV: 1) inhibition of calcium influx by ouabain, a cardiac glycoside toxic to neural stem cells, and 2) targeted inhibition of cyclin-dependent kinase 5 (CDK5), which is restricted to neurons by p35, its activator protein, by TP5. ATRT cell lines and tumor tissue obtained from patients were confirmed for SMARCB1 loss and increased HML-2 ENV. Cell viability and intracellular HML-2 ENV concentration were measured after treatment with ouabain and TP5 (CDK5 antagonist). We evaluated the calcium-mediated effect of ouabain on HML-2 intracellular concentration by treating the cells with ouabain, the calcium chelators calcimycin and EGTA, and calpeptin, a calpain inhibitor, which activates CDK5, and measuring HML-2 ENV and p35. We evaluated HML-2 ENV for a CDK5 consensus phosphorylation site and performed co-immunoprecipitation to evaluate direct interaction. We evaluated activity of CDK5 in ATRT cell lines by autoradiography. Both Ouabain and TP5 caused a decrease in cell viability in a dose-dependent manner. Further, ouabain treatment decreased HML-2 ENV intracellular concentration. We found that HML-2 ENV contains a consensus phosphorylation site for CDK5. We discovered that HML-2 ENV was bound to CDK5. We established that ATRT cell lines had hyperactive CDK5. Finally, we established that the effect of ouabain on HML-2 ENV was due to indirect inhibition of calcium-mediated activation of calpain and thus CDK5.
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Kuo, Min-Yung, Wei-Ting Yang, Yann-Jen Ho, Ge-Man Chang, Hsiung-Hao Chang, Chao-Yu Hsu, Chia-Che Chang, and Yi-Hsin Chen. "Hispolon Methyl Ether, a Hispolon Analog, Suppresses the SRC/STAT3/Survivin Signaling Axis to Induce Cytotoxicity in Human Urinary Bladder Transitional Carcinoma Cell Lines." International Journal of Molecular Sciences 24, no. 1 (December 21, 2022): 138. http://dx.doi.org/10.3390/ijms24010138.
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Bladder cancer is a leading human malignancy worldwide. Signal transducer and activator of transcription (STAT) 3 is an oncogenic transcription factor commonly hyperactivated in most human cancers, including bladder cancer. Notably, preclinical evidence has validated STAT3 blockade as a promising therapeutic strategy for bladder cancer. Hispolon Methyl Ether (HME) is a structural analog of hispolon, an anticancer component of the medicinal mushroom Phellinus linteus. Thus far, HME’s anticancer activity and mechanisms remain largely unknown. We herein report HME was cytotoxic, more potent than cisplatin, and proapoptotic to various human bladder transitional carcinoma cell lines. Of note, HME blocked STAT3 activation, evidenced by HME-elicited reduction in tyrosine 705-phosphorylated STAT3 levels constitutively expressed or induced by interleukin-6. Significantly, HME-induced cytotoxicity was abrogated in cells expressing a dominant-active STAT3 mutant (STAT3-C), confirming STAT3 blockage as a pivotal mechanism of HME’s cytotoxic action. We further revealed that survivin was downregulated by HME, while its levels were rescued in STAT3-C-expressing cells. Moreover, survivin overexpression abolished HME-induced cytotoxicity, illustrating survivin as a central downstream mediator of STAT3 targeted by HME. Lastly, HME was shown to lower tyrosine 416-phosphorylated SRC levels, suggesting that HME inhibits STAT3 by repressing the activation of SRC, a STAT3 upstream kinase. In conclusion, we present the first evidence of HME’s anti-bladder cancer effect, likely proceeding by evoking apoptosis through suppression of the antiapoptotic SRC/STAT3/survivin signaling axis.
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Mastrangelo, M. F., K. G. Weinstock, B. K. Shafer, A. M. Hedge, D. J. Garfinkel, and J. N. Strathern. "Disruption of a silencer domain by a retrotransposon." Genetics 131, no. 3 (July 1, 1992): 519–29. http://dx.doi.org/10.1093/genetics/131.3.519.
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Abstract A galactose-inducible Ty element carrying the HIS3 gene has been used as an insertional mutagen to generate alpha-factor resistant mutants. This collection of Ty-induced mutations includes insertions into the gene for the alpha-factor receptor (STE2), several nonspecific STE genes, and mutations that lead to the expression of the normally silent HML alpha locus. The hml alpha "on" mutations fall into two classes, those that disrupt trans-acting regulators involved in silencing HML alpha and a novel class of mutations that activate HML alpha by insertion at that locus. The hml alpha::Ty "on" mutations illustrate the unusual ability of these retrotransposons to activate genes by overcoming gene silencing mechanisms. The hml alpha::Ty "on" mutations include examples of multimeric Ty arrays. Single Ty and solo delta insertion derivatives of these Ty multimers restore the ability of the silencing mechanism to repress HML alpha.
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Schieferdecker, H. L., R. Ullrich, A. N. Weiss-Breckwoldt, R. Schwarting, H. Stein, E. O. Riecken, and M. Zeitz. "The HML-1 antigen of intestinal lymphocytes is an activation antigen." Journal of Immunology 144, no. 7 (April 1, 1990): 2541–49. http://dx.doi.org/10.4049/jimmunol.144.7.2541.
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Abstract The Ag recognized by the mAb HML-1 is expressed on more than 90% of human intestinal intraepithelial lymphocytes, whereas in other lymphoid tissues it is rarely or not expressed. In the present study, we have investigated the percentage of HML-1-positive cells in the human intestinal lamina propria and the coexpression of HML-1 with different T cell subset markers. In addition, we studied the inducibility of HML-1 on PBL which normally are HML-1-negative. Flow cytometric analysis of isolated intestinal lamina propria lymphocytes (LPL) showed that about 40% of the cells expressed HML-1, the majority belonging to the CD8-positive subpopulation. Virtually all LPL expressed CD45RO, whereas the percentage of CD29-positive cells was only about 50%, similar to PBL. There were only few cells expressing CD45RA or Leu-8 in the lamina propria. HML-1-positive cells were almost exclusively CD45RA-negative, but were found in both the CD29-positive and the CD29-negative subpopulation of LPL. In vitro stimulation of PBL showed that the expression of HML-1 was inducible on T cells by mitogens, phorbolester, Ag, and rIL-2. Expression of HML-1 was induced with a different time course and with differences in the response to the investigated stimuli compared with CD25. Activated HML-1-positive PBL were also predominantly CD45RA-negative. The findings show that HML-1 is an Ag, which is expressed in vivo on a specific subset of previously activated T cells in the unique environment of the intestinal mucosa, and which can be induced in vitro by different activation signals on PBL.
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Lodal, Jan M. "SICBM Yes, HML No." International Security 12, no. 2 (1987): 182. http://dx.doi.org/10.2307/2538820.
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