Miracle-dz/UniFAR-FTUs huggingface dataset:
Small Molecules Targeting Hepatitis C Virus-Encoded NS5A Cause Subcellular Redistribution of Their Target: Insights into Compound Modes of Action

ABSTRACT The current standard of care for hepatitis C virus (HCV)-infected patients consists of lengthy treatment with interferon and ribavirin. To increase the effectiveness of HCV therapy, future regimens will incorporate multiple direct-acting antiviral (DAA) drugs. Recently, the HCV-encoded NS5A protein has emerged as a promising DAA target. Compounds targeting NS5A exhibit remarkable potency in vitro and demonstrate early clinical promise, suggesting that NS5A inhibitors could feature in future DAA combination therapies. Since the mechanisms through which these molecules operate are unknown, we have used NS5A inhibitors as tools to investigate their modes of action. Analysis of replicon-containing cells revealed dramatic phenotypic alterations in NS5A localization following treatment with NS5A inhibitors; NS5A was redistributed from the endoplasmic reticulum to lipid droplets. The NS5A relocalization did not occur in cells treated with other classes of HCV inhibitors, and NS5A-targeting molecules did not cause similar alterations in the localization of other HCV-encoded proteins. Time course analysis of the redistribution of NS5A revealed that the transfer of protein to lipid droplets was concomitant with the onset of inhibition, as judged by the kinetic profiles for these compounds. Furthermore, analysis of the kinetic profile of inhibition for a panel of test molecules permitted the separation of compounds into different kinetic classes based on their modes of action. Results from this approach suggested that NS5A inhibitors perturbed the function of new replication complexes, rather than acting on preformed complexes. Taken together, our data reveal novel biological consequences of NS5A inhibition, which may help enable the development of future assay platforms for the identification of new and/or different NS5A inhibitors.
Ubiquitous activation of Ras and Jak/Stat pathways in human HCC.

BACKGROUND & AIMS Although the natural history and pathologic characteristics of human hepatocellular carcinoma (HCC) are well documented, the molecular pathogenesis of HCC remains poorly understood. Here, we define the role for Ras and Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathways in human HCC. METHODS Promoter and genomic status of Ras and Jak/Stat inhibitors were assessed in 80 HCCs by methylation-specific polymerase chain reaction and microsatellite analysis. Activation of Ras and Jak/Stat signaling pathways was determined by DNA sequencing, Western blot, and immunoprecipitation analysis. Suppression of Ras and Jak/Stat pathways in HCC cell lines was evaluated by viability and apoptosis assays. RESULTS Activation of Ras and Jak/Stat pathways was enhanced in all HCCs when compared with nonneoplastic surrounding and normal livers coincidently with the suppression of at least 1 Ras (RASSF1A and/or NORE1A) and 2 Jak/Stat inhibitors (cytokine-inducible SH2-protein [CIS]; suppressor of cytokine signaling [SOCS]1, 2, 3; and SH2-containing phosphatases [SHP1]). HCC associated with cirrhosis showed significantly higher frequency of RASSF1A, CIS, and SOCS1 promoter methylation than HCC without cirrhosis (P < .002, P < .02, and P < .02, respectively). Furthermore, aberrant methylation of NORE1A and SOCS3 promoters was observed only in a subclass of HCC with poor survival, suggesting that inactivation of these 2 genes might be involved in HCC progression. Combined treatment of HCC cell lines with Ras and Jak/Stat inhibitors as well as with the demethylating agent zebularine induced a strong apoptotic response. CONCLUSIONS These data demonstrate the ubiquitous activation of Ras and Jak/Stat pathways in HCC and suggest the potential use of Ras and Jak/Stat inhibitors and demethylating agents as therapeutic modality for human liver cancer.
[Effect of long-term treatment with inhaled budesonide on adult height of children with asthma].

INTRODUCTION Short-term studies have shown that inhaled corticosteroids may retard the growth of children with asthma. The effect of long-term treatment on adult height is, however, uncertain. MATERIAL AND METHODS We conducted a prospective study of children with asthma to examine the effect of long-term treatment with inhaled budesonide on adult height. We report on 211 children who have attained adult height: 142 asthmatic children treated with budesonide, 18 asthmatic control patients who have never received inhaled corticosteroids, and 51 healthy siblings of patients in the budesonide group, who also served as controls. RESULTS The children in the budesonide group attained adult height after a mean of 9.2 years of budesonide treatment (range 3-13 years) at a mean daily dose of 412 micrograms (range 110-877 micrograms). The mean cumulative dose of budesonide was 1.35 g (range 0.41-3.99 g). The mean differences between the measured and target adult heights were +0.3 cm (95% confidence intervals: -0.6; +1.2 cm) for the children treated with budesonide, -0.2 cm (95% confidence intervals: -2.4; +2.1 cm) for the control children with asthma, and +0.9 cm (95% confidence intervals: -0.4; +2.2 cm) for the healthy siblings. The adult height depended significantly (p < 0.001) on the child's height before budesonide treatment. Although growth rates were significantly reduced during the first years of budesonide treatment, these changes were not significantly associated with adult height. DISCUSSIONS Children with asthma who have received long-term treatment with inhaled budesonide attain normal adult height.
Efficacy of sympathetic influences as related to initial vascular tonicity.

The efficacy of vasoconstrictor influences as dependent on the initial vascular tone (initial rate of perfusion) and perfusion pressure was investigated in rat and frog hindlimb preparations perfused with saline solution. Efficacy was determined as the ratio of the preparation resistance (R) induced by sympathetic stimulation to the initial resistance R0. At a pressure normal for the experimental animal, the relationship between R/R0 and flow is expressed by a dome-shaped curve. At a pressure twice the normal, it is low at all points; at a pressure half the normal, different responses were obtained from the two species used in the experiment: in rats elevation of vascular tone induced by sympathetic stimulation resulted in a complete cessation of flow, whereas in frogs the initial high efficacy diminished with increasing vascular tone. A mathematical model devised to study the dependence of the efficacy of sympathetic stimulation on initial tonicity is described. The good consistency of experimental and calculated results is regarded as evidence that the prerequisites stipulated in the model, i.e., the capacity of closure and the heterogeneity of arterioles, in regard to the effort developed by their smooth muscle, are actually inherent in the vascular system of organs.
Biofilm formation by Pseudomonas aeruginosa wild type, flagella and type IV pili mutants

Biofilm formation by Gfp‐tagged Pseudomonas aeruginosa PAO1 wild type, flagella and type IV pili mutants in flow chambers irrigated with citrate minimal medium was characterized by the use of confocal laser scanning microscopy and comstat image analysis. Flagella and type IV pili were not necessary for P. aeruginosa initial attachment or biofilm formation, but the cell appendages had roles in biofilm development, as wild type, flagella and type IV pili mutants formed biofilms with different structures. Dynamics and selection during biofilm formation were investigated by tagging the wild type and flagella/type IV mutants with Yfp and Cfp and performing time‐lapse confocal laser scanning microscopy in mixed colour biofilms. The initial microcolony formation occurred by clonal growth, after which wild‐type P. aeruginosa bacteria spread over the substratum by means of twitching motility. The wild‐type biofilms were dynamic compositions with extensive motility, competition and selection occurring during development. Bacterial migration prevented the formation of larger microcolonial structures in the wild‐type biofilms. The results are discussed in relation to the current model for P. aeruginosa biofilm development.
Unique Cell Surface Expression of Receptor Tyrosine Kinase ROR1 in Human B-Cell Chronic Lymphocytic Leukemia

Purpose: Gene expression profiling identified receptor tyrosine kinase ROR1, an embryonic protein involved in organogenesis, as a signature gene in B-cell chronic lymphocytic leukemia (B-CLL). To assess the suitability of ROR1 as a cell surface antigen for targeted therapy of B-CLL, we carried out a comprehensive analysis of ROR1 protein expression. Experimental Design: Peripheral blood mononuclear cells, sera, and other adult tissues from B-CLL patients and healthy donors were analyzed qualitatively and quantitatively for ROR1 protein expression by flow cytometry, cell surface biotinylation, Western blotting, and ELISA. Results: ROR1 protein is selectively expressed on the surface of B-CLL cells, whereas normal B cells, other normal blood cells, and normal adult tissues do not express cell surface ROR1. Moreover, cell surface expression of ROR1 is uniform and constitutive, i.e., independent of anatomic niches, independent of biological and clinical heterogeneity of B-CLL, independent of B-cell activation, and found at similar levels in all B-CLL samples tested. The antibody binding capacity of B-CLL cell surface ROR1 was determined to be in the range of 103 to 104 molecules per cell. A portion of B-CLL cell surface ROR1 was actively internalized upon antibody binding. Soluble ROR1 protein was detectable in sera of <25% of B-CLL patients and a similar fraction of healthy donors at concentrations below 200 ng/mL. Conclusions: The restricted, uniform, and constitutive cell surface expression of ROR1 protein in B-CLL provides a strong incentive for the development of targeted therapeutics such as monoclonal antibodies.
Automatic liver segmentation from multiphase CT images by using level set method

Segmentation of liver from Multi-phase CT images is one of the essential technology for computer aided diagnosis. Contrast medium gives multi-phase CT images different intensity feature which enables to detect tumor. It is a challenging problem to segment liver region from multi-phase CT images. There are many approaches for solving this problem, however, these methods depend on other phases or registration. In order to solve this problem, we propose anatomy feature-based method which is mostly independent for each phase in this paper. This method uses level set method for final segmentation. The accuracy of segmentation result by level set methods relay on initial contour, so we preprocess initial region of liver by anatomical feature. Then we introduced contour constrain by using ribs information to improve segmentaion accuracy. Our segmentation was evaluated on 5 multi-phase CT images which have 4 phases. Experimental results show that the proposed method is good accuracy for each phase.
Factors favoring successful transmetatarsal amputation in diabetes.

ALTHOUGH the emergency character of infectious or early gangrenous lesions of the toes and feet of diabetic patients has long been recognized by most physicians, a new aspect of this problem is presented by the demonstration that in many diabetic patients a useful and serviceable foot can be preserved through the proper use of the transmetatarsal amputation.1 , 2 Actually, in the last two years major amputations above the ankle have become less frequent at the New England Deaconess Hospital (Table 1). The danger inherent in minor lesions and the importance of teaching all older diabetic patients simple prophylactic measures appeared time .
Performance and costs of particle air filtration technologies.

This paper predicts the reductions in the indoor mass concentrations of particles attainable from use of filters in building supply airstreams and also from use of stand-alone fan-filter units. Filters with a wide efficiency range are considered. Predicted concentration reductions are provided for indoor-generated particles containing dust-mite and cat allergen, for environmental tobacco smoke (ETS) particles, and for outdoor air fine-mode particles. Additionally, this paper uses a simple model and available data to estimate the energy and total costs of the filtration options. Predicted reductions in cat and dust-mite allergen concentrations range from 20 to 80%. To obtain substantial, e.g. 50%, reductions in indoor concentrations of these allergens, the rate of airflow through the filter must be at least a few indoor volumes per hour. Increasing filter efficiencies above approximately ASHRAE Dust Spot 65% does not significantly reduce predicted indoor concentrations of these allergens. For ETS particles and outdoor fine-mode particles, calculations indicate that relatively large, e.g. 80%, decreases in indoor concentrations are attainable with practical filter efficiencies and flow rates. Increasing the filter efficiency above ASHRAE 85% results in only modest predicted incremental decreases in indoor concentration. Energy costs and total costs can be similar for filtration using filters with a wide range of efficiency ratings. Total estimated filtration costs of approximately $0.70 to $1.80 per person per month are insignificant relative to salaries, rent, or health insurance costs.
Ag‐bearing liposomes engrafted with peptides that interact with CD11c/CD18 induce potent Ag‐specific and antitumor immunity

Dendritic cells (DCs) play key role in eliciting antigen (Ag)‐specific immune responses, and crucial to this is the uptake of Ag via surface receptors including the heterodimeric integrin CD11c/CD18. Here we report that CD11c/CD18‐interacting peptides can be used as targeting moieties to deliver liposomal Ag to antigen presenting cells (APCs) and elicit Ag‐specific and antitumor immunity. Two peptides of sequence related to human ICAM‐4 and previously reported to bind CD11c/CD18, and a 12‐mer cyclic peptide previously identified by phage display to bind CD11c/CD18, were produced synthetically, and tested for their ability to target liposomal Ag. The three peptides were designed to contain a shorter spacer to reduce steric hindrance, and a His‐tag to enable engraftment onto liposomes incorporated with chelator lipid. Our results show that the three peptides, denoted as p17, p18 and p30, promote strong binding of liposomes to CD11c+ and CD11b+ cells in vitro and in vivo. Vaccination of mice with Ag‐bearing liposomes engrafted with the peptides, particularly p18 and p30, induced Ag‐specific T cell priming and antibody production. Importantly, the vaccination of C57BL/6 mice with syngeneic B16‐OVA‐derived plasma membrane vesicles (PMVs) engrafted with p18 and p30 peptide showed dramatic antitumor responses, inhibiting tumor growth/metastasis in both the lung and subcutaneous tumor models, with a high proportion of the mice apparently being “cured” of their tumors. The engraftment of p18 and p30 peptides onto liposomes and PMVs, thus provides an effective means to target Ags to DCs in vivo, for the development of effective cancer vaccines and immunotherapies.
Internal model control (IMC) approach for designing disk drive servo-controller

This paper presents the design procedure for disk drive servomechanism using internal model control (IMC) structure. A typical disk drive actuator can be modeled as a second order dynamics for low frequencies. However, the higher frequency response shows resonant behavior which are difficult to model. We discuss the use of IMC structure for designing servo-controllers for disk drives. In this method, a second order nominal model of the plant is used to design an H/sub 2/-optimal controller to attain minimum integral-error-square (ISE) performance. Multiplicative uncertainty bound is defined by the difference between the actual frequency response and the response of the nominal model. The uncertainty bound is used to decide robust stability and robust performance bounds. The H/sub 2/-optimal control is then augmented by a low-pass filter with sufficient high frequency roll-off to ensure robust stability and robust performance. Tuning of only one parameter of the IMC filter makes this design method easy and convenient. Simulation results for the designed controller are presented. <<ETX>>
Reciprocal EMG control of elbow extension by FES

Elbow extension is critical in performing activities of daily living. Individuals with a C5-C6 spinal cord injury have paralyzed elbow extensors, yet retain weak to strong voluntary control of elbow flexion. Previous studies have shown that functional electrical stimulation (FES) of the triceps provides sufficient elbow extension strength and control to greatly improve function. With triceps stimulation applied at a constant level, elbow angle is controlled naturally by voluntary flexion opposing the stimulated extension-referred to as voluntary antagonist control. We have investigated an alternative reciprocal control scheme employing biceps electromyogram. (EMG) to modulate triceps stimulation. With reciprocal control, increasing biceps EMG proportionally reduces triceps stimulation. A personal computer (PC)-based lab system was designed to test the feasibility of reciprocal control. Reciprocal control increased the range of elbow moments, was stable during maintained elbow angle or isometric moment, and used less stimulation. Reciprocal control of triceps stimulation using biceps EMG is an effective method for restoring elbow extension to C5-C6 spinal cord injury patients, and could be extended to other situations where a voluntarily controlled muscle can be opposed by stimulating an antagonist.
Ecology-based tourism potential of Altindere Valley (Trabzon-Turkey) in regards to the natural, historical and cultural factors

ABSTRACT The study was carried out in the Altindere Valley, which is an area appropriate for tourism activities with natural, historical and cultural values through all four seasons, with Yazlik Village in the centre and including the surrounding sites Cosandere village, Altindere village, hamlets (The Hamlets) and plateau areas. In this study, the goal is to set forth the ecological-based tourism potential in line with the concepts of intactness; conservation-use balance; and sustainability at natural, historical and cultural sites through a determined planning approach. In this respect, assessments have been made on the study area on the basis of the ‘Ecological Evaluation Method’, which has been developed for urban areas. Through the determination of quotients, classification and quantitative assessment of unweighted values were found for natural and cultural elements that show percentage (%) dispersion at the area (slope, exposition, soil, forest, vegetation, existing areas use, historical and cultural structure). ‘Weighted values’ were calculated by multiplying the determined factor weights and the unweighted inside grid values of the factors. With the results of grid values obtained, 10.58% Very Good, 48.82% Good, 19.7% Average, 8.82% Weak, and 12.05% Very Weak, ‘Ecological Based Tourism Potential Areas According to Natural, Historical and Cultural Factors’ have been identified.
Looking for the Optimum Credit Burden as a Percentage of GDP so as to Minimize NPLs: A Panel Data Analysis in All Industrialized Countries

The findings of the present paper hint that there is a limit on the burden of debt, thus suggesting that borrowers cannot afford a loan burden beyond a certain critical level. Perhaps, this critical level could be considered as the Achilles heel of the capitalism. It also hints that there is a conflict in economic policy: either borrowers will collapse or banks will collapse. The sample covers all industrialized countries. Data are taken from World Bank. The elaboration of these panel data is made feasible by means of the E-views software package.
Isoform‐specific expression of 14‐3‐3 proteins in human lung cancer tissues

14‐3‐3 Proteins play important roles in a wide range of vital regulatory processes, including signal transduction, apoptosis, cell cycle progression and DNA replication. In mammalian cells, 7 14‐3‐3 isoforms (β, γ, ϵ, η, σ, θ and ζ) have been identified and each of these seems to have distinct tissue localizations and isoform‐specific functions. Previous studies have shown that 14‐3‐3 protein levels are higher in human lung cancers as compared to normal tissues. It is unclear, however, which of the 14‐3‐3 isoform(s) are overexpressed in these cancers. In our study, the levels of all seven 14‐3‐3 isoforms were examined by RT‐PCR and Western blotting. We show that the message for only two isoforms, 14‐3‐3ϵ and ζ, could be detected in normal tissues. In lung cancer biopsies, however, four isoforms, 14‐3‐3β, γ, σ, and θ, in addition to 14‐3‐3ϵ and ζ, were present in abundance. The expression frequency of 14‐3‐3β, γ, σ and θ isoforms was 11, 10, 13 and 8 of the 14 biopsies examined, respectively. The data from immunohistochemical staining and Western blotting were consistent with the RT‐PCR results. Given the prevalence of elevated 14‐3‐3 expression in human lung cancers we propose that these proteins may be involved in lung cancer tumorigenesis and that specific 14‐3‐3 proteins may be useful as markers for lung cancer diagnosis and targets for therapy.
Differential reaction of fast and slow alpha-motoneurones to axotomy.

1. The properties of medial gastrocnemius (m.g., fast alpha) and soleus (sol., slow alpha) motoneurones of the cat were examined with intracellular electrodes 8-119 days after section of the muscle nerves.2. The axonal conduction velocity was significantly decreased in both m.g. and sol. motoneurones after chronic section of the muscle nerves.3. The amplitude of overshoot of action potentials was significantly increased in both m.g. and sol. motoneurones following section of the muscle nerves.4. No significant changes in the resting membrane potential or the input resistance were observed for sol. motoneurones, whereas m.g. motoneurones showed a slight decrease in the resting potential and a slight increase in the input resistance.5. The duration of after-hyperpolarization was significantly decreased in sol. motoneurones, whereas that in m.g. motoneurones remained virtually unchanged or increased slightly following section of the muscle nerves.6. The changes described above were not seen in the preparations examined 29-46 days after section of the lumbosacral dorsal roots, suggesting that alterations in the motoneurone properties observed after section of the muscle nerves resulted from axotomy of the motoneurones rather than from sensory deprivation.7. The differences in electrophysiological properties between m.g. and sol. motoneurones were less prominent in axotomized animals than in control, unoperated cats.8. It is concluded that fast (m.g.) and slow (sol.) alpha-motoneurones have qualitatively different properties. A possible ;dedifferentiation' of fast and slow alpha-motoneurones by axotomy is discussed.
A Meromorphic Model for Discouraging Corruption in Public Organizations

Corruption is a flagrant violation of the norms of trust and professional standards. What organizations do internally to prevent corruption is very important in the global equation of corruption control. In this paper, we propose to understand corruption as a phenomenon that can be discouraged; we use this insight to imagine people as neither already corrupt nor inherently corruptible and propose a meromorphic model for discouraging corruption in organizations. Our model can help improve the effectiveness of organization leaders with respect to discouraging corruption, and can be used in education and training programs. The model can also be expanded by adding new dimensions, as considered appropriate, and can form a basis for empirical research.