Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential regulation of mouse equilibrative nucleoside transporter 1 (mENT1) splice variants by protein kinase CK2

Nucleosides are accumulated by cells via a family of equilibrative transport proteins (ENTs). An alternative splice variant of the most common subtype of mouse ENT (ENT1) has been identified which is missing a protein kinase CK2 (casein kinase 2) consensus site (Ser254) in the central intracellular loop of the protein. We hypothesized that this variant (mENT1a) would be less susceptible to modulation by CK2-mediated phosphorylation compared to the variant containing the serine at position 254 (mENT1b). Each splice variant was transfected into nucleoside transporter deficient PK15 cells, and stable transfectants assessed for their ability to bind the ENT1-selective probe [3H]nitrobenzylthioinosine (NBMPR) and to mediate the cellular uptake of [3H]2-chloroadenosine, with or without treatment with the CK2 selective inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBB). mENT1a had a higher affinity for NBMPR relative to mENT1b – measured both directly by the binding of [3H]NBMPR, and indirectly via inhibition of [3H]2-chloroadenosine influx by NBMPR. Furthermore, incubation of mENT1b-expressing cells with 10 µM TBB for 48 h decreased both the KD and Bmax of [3H]NBMPR binding, as well as the Vmax of 2-chloroadenosine uptake, whereas similar treatment of mENT1a-expressing cells with TBB had no effect. PK15 cells transfected with hENT1, which has Ser254, was similar to mENT1b in its response to TBB. In conclusion, inhibition of CK2 activity, or deletion of Ser254 from mENT1, enhances transporter affinity for the inhibitor, NBMPR, and reduces the number of ENT1 proteins functioning at the level of the plasma membrane.
Regulation of Hepatitis B Virus Replication by the Phosphatidylinositol 3-Kinase-Akt Signal Transduction Pathway

ABSTRACT The phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway is one of the major oncogenic pathways and is activated in many types of human cancers, including hepatocellular carcinoma. It can also be activated by the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein. In the present study, we set out to determine the regulatory effects of this pathway on the replication of hepatitis B virus (HBV). Our results demonstrate that the expression of a constitutively active Akt1 profoundly inhibited HBV RNA transcription and consequently reduced HBV DNA replication in HepG2 cells. This suppression of HBV gene transcription was apparently mediated by the activation of mTOR, as it was abolished by the mTOR inhibitor rapamycin. Moreover, treatment of HBV-expressing HepG2.2. 15 cells with inhibitors of PI3K, Akt, and mTOR increased the transcription of 3.5-kb and 2.4-kb viral RNA as well as the replication of HBV DNA. This observation implies that the basal level activation of this pathway in HepG2 cells regulated HBV replication. Consistent with previous reports showing that the HCV NS5A protein could bind to the p85 subunit of PI3K and activate the PI3K-Akt signal transduction pathway, our results showed that expression of this protein could inhibit HBV RNA transcription and reduce HBV DNA replication in HepG2 cells. Taken together, our results suggest that the activation of the PI3K-Akt pathway during liver oncogenesis may be at least partially responsible for the elimination of HBV replication from tumor cells and may also provide an explanation for the observed suppression of HBV replication by HCV coinfection.
Recruitment of the NCoA/SRC-1/p160 Family of Transcriptional Coactivators by the Aryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Complex

ABSTRACT The aryl hydrocarbon receptor complex heterodimeric transcription factor, comprising the basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins, mediates the toxic effects of TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin). The molecular events underlying TCDD-inducible gene activation, beyond the activation of the AHRC, are poorly understood. The SRC-1/NCoA-1, NCoA-2/GRIP-1/TIF-2, and p/CIP/AIB/ACTR proteins have been shown to act as mediators of transcriptional activation. In this report, we demonstrate that SRC-1, NCoA-2, and p/CIP are capable of independently enhancing TCDD-dependent induction of a luciferase reporter gene by the AHR/ARNT dimer. Furthermore, injection of anti-SRC-1 or anti-p/CIP immunoglobulin G into mammalian cells abolishes the transcriptional activity of a TCDD-dependent reporter gene. We demonstrate by coimmunoprecipitation and by a reporter gene assay that SRC-1 and NCoA-2 but not p/CIP are capable of interacting with ARNT in vivo after transient transfection into mammalian cells, while AHR is capable of interacting with all three coactivators. We confirm the interactions of ARNT and AHR with SRC-1 with immunocytochemical techniques. Furthermore, SRC-1, NCoA-2, and p/CIP all associate with the CYP1A1 enhancer region in a TCDD-dependent fashion, as demonstrated by chromatin immunoprecipitation assays. We demonstrate by yeast two-hybrid, glutathione S-transferase pulldown, and mammalian reporter gene assays that ARNT requires its helix 2 domain but not its transactivation domain to interact with SRC-1. This indicates a novel mechanism of action for SRC-1. SRC-1 does not require its bHLH-PAS domain to interact with ARNT or AHR, but utilizes distinct domains proximal to its p300/CBP interaction domain. Taken together, these data support a role for the SRC family of transcriptional coactivators in TCDD-dependent gene regulation.
The Middle Class in Mozambique

In recent years, the growth of a middle class has been a key feature of the 'Africa Rising' narrative. Here, Sumich explores the formation of this middle class in Mozambique, answering questions about the basis of the class system and the social order that gives rise to it. Drawing extensively on his fieldwork, Sumich argues that power and status in dominant party states like Mozambique derives more from the ability to access resources, rather than from direct control of the means of production. By considering the role of the state, he shows how the Mozambican middle class can both be bound to a system they benefit from and alienated from it at the same time, as well as exploring the ways in which the middle classes attempt to reproduce their positions of privilege and highlighting the deep uncertain future that they face.
Direct immunofluorescence in cutaneous vesiculobullous lesions.

UNLABELLED Direct Immunofluorescence (DIF) is invaluable in the diagnosis of cutaneous vesiculobullous lesions (VBL). It is limited by technical factors and disease nature. 1) To record the sensitivity of DIF in VBL 2) To correlate DIF with clinical, histologic findings and analyse discrepancies. MATERIAL AND METHODS A retrospective study of 100 DIFs on suspected VBL of skin. DIF, histology and clinical data were reviewed. 73/100 cases showed DIF patterns concordant with clinical/histologic diagnosis. The sensitivity of DIF was 88% in Pemphigus group (39/ 44), 82% in Bullous Pemphigoid (BP) (23/28), and 20% in Dermatitis Herpetiformis (DH) (1/5). 18 cases of histologically proven VBL were negative and of these, 4 had no epidermis. The remaining 9 cases were discordant with clinical/histologic features, including 4 BP and 5 DH, whose histology was non-specific and will be discussed in detail. One case of DH showed an aberrant vasculitic pattern. DIF is of great value in the diagnosis of VBL, specially in clinical/histologic dilemmas. In DH, neither biopsy nor DIF were very useful and response to therapy was the standard. Sampling errors contributed to false negative results. Proper selection of cases and judicious use are mandatory to optimize its' utility.
N‐acetylcysteine stimulates osteoblastic differentiation of mouse calvarial cells

Estrogen deficiency causes osteoporosis via increased generation of reactive oxygen species (ROS), and thus, antioxidants may prove to be the effective therapeutic candidates. We examined the effects of the antioxidant N‐acetylcysteine (NAC) on osteoblastic differentiation in mouse calvarial cells. NAC (10–30 mM) enhanced alkaline phosphatase activity, mRNA expression of osteoblast differentiation‐associated genes and mineralized nodule formation. It also increased expression of bone morphogenetic proteins‐2, ‐4, and ‐7. The osteogenic activity of NAC was partially reduced by inhibition of glutathione synthesis. Since caffeic acid phenethyl ester did not stimulate osteoblast differentiation, it is unlikely that ROS scavenging activity of NAC is sufficient for osteogenic activity. We observed that NAC suppressed small GTPase RhoA activity and activation of RhoA by Pasteurella multocida toxin suppressed the osteogenic activity of NAC. These results suggest that NAC might exert its osteogenic activity via increased glutathione synthesis and inhibition of RhoA activation. J. Cell. Biochem. 103: 1246–1255, 2008. © 2007 Wiley‐Liss, Inc.
Concomitant Helper Response Rescues Otherwise Low Avidity CD8+ Memory CTLs to Become Efficient Effectors In Vivo1

This report seeks a means of maximizing memory CD8 T cell responses to peptide immunization. Delivery of the CD8 peptide epitope by stress protein, heat shock protein (hsp)70, results in excellent immunogenicity at the acute phase but memory responses were poor both in terms of the number of responding cells as well as their functional avidity. We demonstrate for the first time that hsp70 can also be used as a vehicle to achieve CD4 T cell responses to loaded peptide epitopes and that coimmunization with hsp70 loaded with both CD8 and CD4 peptide epitopes may increase memory up to 3-fold. Furthermore, CD8+ T cell memory responses were of higher avidity measured both by in vitro cytotoxicity assays and a new methodology that measures the avidity of CTL activity in vivo in mice. Our results emphasize that peptide immunization remains a viable approach to induce long-term CD8+ T cell function, providing steps are taken to assure appropriate stimulation of Th cell responses.
Trends in waiting list registration for liver transplantation for viral hepatitis in the United States.

BACKGROUND & AIMS In the last decade, significant progress has been made in the treatment of liver disease associated with chronic hepatitis, especially in patients infected with the hepatitis B virus (HBV). To investigate whether the population-wide application of antiviral therapies has impacted liver transplant waiting list registration, we analyzed longitudinal trends in waiting list registration for patients with hepatitis B and C and those with nonviral liver disease. METHODS This study represented a retrospective analysis of registry data containing all US liver transplant centers. All adult, primary liver transplantation candidates registered to the Organ Procurement and Transplantation Network between 1985 and 2006 were included in the analysis. Standardized incidence rates were calculated for waiting list registration for liver transplantation by underlying disease (HBV and HCV infection and other) and by indication for transplantation (fulminant liver disease, hepatocellular carcinoma [HCC], and end-stage liver disease [ESLD]). RESULTS Of 113,927 unique waiting list registrants, 4793 (4.2%) had HBV, and 40,923 (35.9%) had HCV infections; the remaining 68,211 (59.9%) had neither. The incidence of waiting list registration for ESLD and fulminant liver disease decreased, whereas that for HCC increased. The decrease in ESLD registration was most pronounced, and the increase in HCC was least dramatic among registrants with hepatitis B. The decrease in registration for ESLD secondary to HCV infection was also significantly larger than that for ESLD patients with nonviral etiologies. CONCLUSIONS The pattern of liver transplantation waiting list registration among patients with hepatitis B suggests that the widespread application of oral antiviral therapy for HBV contributed to the decreased incidence of decompensated liver disease.
Foresight: Rapid Data Exploration Through Guideposts

Current tools for exploratory data analysis (EDA) require users to manually select data attributes, statistical computations and visual encodings. This can be daunting for large-scale, complex data. We introduce Foresight, a visualization recommender system that helps the user rapidly explore large high-dimensional datasets through "guideposts. " A guidepost is a visualization corresponding to a pronounced instance of a statistical descriptor of the underlying data, such as a strong linear correlation between two attributes, high skewness or concentration about the mean of a single attribute, or a strong clustering of values. For each descriptor, Foresight initially presents visualizations of the "strongest" instances, based on an appropriate ranking metric. Given these initial guideposts, the user can then look at "nearby" guideposts by issuing "guidepost queries" containing constraints on metric type, metric strength, data attributes, and data values. Thus, the user can directly explore the network of guideposts, rather than the overwhelming space of data attributes and visual encodings. Foresight also provides for each descriptor a global visualization of ranking-metric values to both help orient the user and ensure a thorough exploration process. Foresight facilitates interactive exploration of large datasets using fast, approximate sketching to compute ranking metrics. We also contribute insights on EDA practices of data scientists, summarizing results from an interview study we conducted to inform the design of Foresight.
Volume weighted volatility: empirical evidence for a new realised volatility measure

We introduce a new conceptually superior realised volatility estimator, volume weighted volatility (VWV), which effectively measures demand-based volatility, rather than only measuring the variability of a price series. We compare the VWV to other return- and range-based measures using the stock index futures, with our results supporting the empirical uniqueness of VWV. First, regressions show that the VWV provides unique information. Second, VWV is (only) weakly associated with other volatility measures for the smallest four volatility quintiles. Third, correlograms illustrate that the VWV is less persistent than the other measures, leading to more unique volatility values. Finally, the VWV most closely approximates the normal distribution.
Sustained Improvements in Dynamic Balance and Landing Mechanics After a 6-Week Neuromuscular Training Program in College Women's Basketball Players.

CONTEXT Epidemiological data demonstrate the need for lower-extremity injury-prevention training. Neuromuscular-control (NMC) programs are immediately effective at minimizing lower-extremity injury risk and improving sport-related performance measures. Research investigating lasting effects after an injury-prevention program is limited. OBJECTIVE To determine whether dynamic balance, landing mechanics, and hamstring and quadriceps strength could be improved after a 6-wk NMC intervention and maintained for a season. DESIGN Prospective case series. SETTING Controlled laboratory. PARTICIPANTS 11 Division I women's basketball players (age 19.40 ± 1.35 y, height 178.05 ± 7.52 cm, mass 72.86 ± 10.70 kg). INTERVENTIONS Subjects underwent testing 3 times, completing the Star Excursion Balance Test (SEBT), Landing Error Scoring System (LESS), and isometric strength testing for the hamstrings and quadriceps muscles. Pretest and posttest 1 occurred immediately before and after the intervention, respectively, and posttest 2 at the end of the competitive season, 9 mo after posttest 1. Subjects participated in eighteen 30-min plyometric and NMC-training sessions over a 6-wk period. MAIN OUTCOME MEASURES The normalized SEBT composite score, normalized peak isometric hamstrings:quadriceps (H:Q) ratio, and the LESS total score. RESULTS The mean composite reach significantly improved over time (F2,10 = 6.96, P = .005) where both posttest scores were significantly higher than pretest (70.41% ± 4.08%) (posttest 1 73.48% ± 4.19%, t10 = -3.11, P = .011) and posttest 2 (74.2% ± 4.77%, t10 = -3.78, P = .004). LESS scores significantly improved over time (F2,10 = 6.29, P = .009). The pretest LESS score (7.30 ± 3.40) was higher than posttest 1 (4.9 ± 1.20, t10 = 2.71, P = .024) and posttest 2 (5.44 ± 1.83, t10 = 2.58, P = .030). There were no statistically significant differences (P > .05) over time for the H:Q ratio when averaging both legs (F2,10 = 0.83, P = .45). CONCLUSIONS A 6-wk NMC program improved landing mechanics and dynamic balance over a 9-mo period in women's basketball players. NMC adaptations can be retained without an in-season maintenance program.
[Follow-up CT measurement of liver malignoma according to RECIST and WHO vs. volumetry].

PURPOSE Intraindividual comparison of quantitative malignant liver tumor response analysis using computed tomography. The RECIST and WHO evaluation results were compared to the volumetry results. MATERIALS AND METHOD Consecutive CT follow-up investigations (portal-venous phase, collimation 3 mm, increment 2 mm) of 82 patients were analyzed retrospectively. The median interval was 56 (30 - 455) days. The patients showed a total of 198 (median 3, range 1 - 5) malignant liver lesions. The evaluation was performed by 2 radiologists using the OncoTREAT software (Mevis) in consensus. The results were classified according to RECIST (Response Evaluation Criteria in Solid Tumors, stable disease: - 30 % to + 20 %) and WHO (stable: - 50 % to + 25 %) and compared to the volumetric analysis (stable: - 65 % to + 44 %). Both the continual follow-up changes and the classified results (complete and partial remission, no change and progression) were analyzed. RESULTS The classified RECIST and WHO results agreed with the volumetric analysis in 71/82 (87 %) of cases kappa (RECIST) = 0,699, kappa (WHO) = 0,741). This included different patients thus showing the agreement between the RECIST and WHO evaluations in 68/82 (83 %) cases (kappa = 0,656). The estimation of the relative tumor development was clearly different in all procedures. Relative tumor changes are not directly comparable because of underlying one-, two- and three-dimensional structures. CONCLUSION If the tumor size is regarded as a suitable parameter of tumor development, quantifying procedures according to RECIST and WHO are of limited use. Relatively reliable tumor response evaluation can only take place by means of thin section investigation and volumetric analysis on the basis of digital image data.
Which Manufacturing Industries and Sectors are Most Vulnerable to Brexit?

When the UK leaves the EU, trade arrangements between the UK and EU will change. Most of the options for future UK‐EU relationships currently under discussion imply increased trade barriers, which will reduce trade and also have effects on output and prices. In this paper, we use a multi‐market partial equilibrium model to analyse the vulnerability of 122 manufacturing industries to Brexit. In all five Brexit scenarios we model, there is an overall reduction in UK manufacturing output. Output grows in some industries but at the expense of higher consumer and intermediate goods prices. High tech and medium–high tech sectors are more at risk of a decline in domestic production than lower tech sectors. In most areas of the country, demand for high‐skilled workers falls more than for medium and low‐skilled workers.
Strategies of Digital Fundus Photography for Screening Diabetic Retinopathy in a Diabetic Population in Urban China

Purpose: To evaluate the effect of mydriasis and different field strategies on technical failure, probability to refer diabetic retinopathy (DR, sensitivity) and probability not to refer patients without DR (specificity) of digital photography in screening with a fundus camera. Methods: A total of 531 patients with diabetes underwent fundus photography with cross-combinations of mydriasis/nonmydriasis and single-field/two-field strategies, followed by slit lamp biomicroscopic examination by a trained ophthalmologist. Fundus photographs were graded independently by another experienced ophthalmologist. Calculations were first based on cases with non-gradable images treated as being referred and then with them excluded. Results: Percentages of DR and referable DR in this patient cohort were 22.4% and 7.7%, respectively, based on slit lamp biomicroscopic examination. Mydriasis significantly reduced the technical failure rate from 27.1% to 8.3% under a single-field strategy, and from 28.2% to 8.9% under a two-field strategy. As compared to the single-field strategy, the two-field strategy increased sensitivity from 75.6% to 87.8% without mydriasis and from 73.2% to 90.2% with mydriasis. Mydriasis increased specificity from 68.8% to 84.3% in the single-field strategy and from 64.7% to 81.6% in the two-field strategy. Had the subjects with non-gradable images been excluded, the two-field strategy without mydriasis reported sensitivity of 85.7% and specificity of 91.6%. Conclusions: Both mydriasis and the two-field strategy are useful in photographic screening tests. Technical failure should be taken into consideration when screening strategies for DR are determined.
Suicidal Plans in Patients With Stroke: Comparison Between Acute-Onset and Delayed-Onset Suicidal Plans

Three hundred one patients were examined for suicidal plans during the acute hospital period following stroke and at 3, 6, 12, and 24 months' follow-up. It was found that 6.6% of patients developed suicidal plans during the initial in-hospital evaluation (acute-onset suicidal plans) and 11.3% of patients developed suicidal plans at 3, 6, 12, or 24 months' follow-up (delayed-onset suicidal plans). The development of both acute and delayed-onset suicidal plans was strongly related to the existence of depressive disorders, especially major depression, and to a prior history of stroke. Acute-onset suicidal plans were also related to premorbid alcohol abuse. Acute-onset suicidal patients had more anterior lesion location and delayed-onset suicidal patients had more posterior stroke lesions. Delayed-onset suicidal plans were not related to alcohol abuse but tended to be associated with greater physical impairment and poorer social support during the acute poststroke period. These data suggest that the etiology of these two types of suicidal plans may be different with acute onset related to biological mechanisms and delayed onset related to psychological mechanisms.
Implanted Adipose‐Derived Stem Cells Attenuate Small‐for‐Size Liver Graft Injury by Secretion of VEGF in Rats

Graft injury after small‐for‐size liver transplantation impairs graft function and threatens the survival of the recipients. The use of adipose‐derived stem cells (ADSCs) for liver injury protection and repair is promising. Our aim was to investigate the role of vascular endothelial growth factor (VEGF) secreted by ADSCs in the treatment of small‐for‐size liver graft injury. Studies were performed using ADSCs with VEGF secretion blocked by RNA interference. In vitro, ADSCs prevented apoptosis of freshly isolated liver sinusoidal endothelial cells (LSECs) by secretion of VEGF. Syngeneic 35% orthotopic liver transplantation followed by implantation of syngeneic ADSCs through the portal vein system was performed using Wistar rats. We found VEGF secreted by implanted ADSCs improved graft microcirculatory disturbances, serum liver function parameters and survival. The improved microcirculatory status was also reflected by reduced hepatocellular damage, especially LSEC apoptosis and improved liver regeneration. These effects were accompanied by decreased expression of endothelin receptor type A, increased Bcl‐2/Bax ratio, decreased expression of Bad and elevated proportion of phosphorylated Bad. In conclusion, implanted syngeneic ADSCs attenuated small‐for‐size liver graft injuries and subsequently enhanced liver regeneration in a rat 35% liver transplantation model. The VEGF secreted by implanted ADSCs played a crucial role in this process.