Miracle-dz/UniFAR-FTUs huggingface dataset:
Exogenous Interleukin-2 Administration Corrects the Cell Cycle Perturbation of Lymphocytes from Human Immunodeficiency Virus-Infected Individuals

ABSTRACT Human immunodeficiency virus (HIV)-induced immunodeficiency is characterized by progressive loss of CD4+ T cells associated with functional abnormalities of the surviving lymphocytes. Increased susceptibility to apoptosis and loss of proper cell cycle control can be observed in lymphocytes from HIV-infected individuals and may contribute to the lymphocyte dysfunction of AIDS patients. To better understand the relation between T-cell activation, apoptosis, and cell cycle perturbation, we studied the effect of exogenous interleukin-2 (IL-2) administration on the intracellular turnover of phase-dependent proteins. Circulating T cells from HIV-infected patients display a marked discrepancy between a metabolic profile typical of G0 and a pattern of expression of phase-dependent proteins that indicates a more-advanced position within the cell cycle. This discrepancy is enhanced by in vitro activation with ConA and ultimately results in a marked increase of apoptotic events. Conversely, treatment of lymphocytes with IL-2 alone restores the phase-specific pattern of expression of cell cycle-dependent proteins and is associated with low levels of apoptosis. Interestingly, exogenous IL-2 administration normalizes the overall intracellular protein turnover, as measured by protein synthesis, half-life of newly synthesised proteins, and total protein ubiquitination, thus providing a possible explanation for the effect of IL-2 on the intracellular kinetics of cell cycle-dependent proteins. The beneficial effect of IL-2 administration is consistent with the possibility of defective IL-2 function in vivo, which is confirmed by the observation that lymphocytes from HIV-infected patients show abnormal endogenous IL-2 paracrine/autocrine function upon in vitro mitogen stimulation. Overall these results confirm that perturbation of cell cycle control contributes to HIV-related lymphocyte dysfunction and, by showing that IL-2 administration can revert this perturbation, suggest a new mechanism of action of IL-2 therapy in HIV-infected patients.
ULTRALOW-DOSE ALPHA-INTERFERON PLUS RIBAVIRIN FOR THE TREATMENT OF ACTIVE HEPATITIS C IN RENAL TRANSPLANT RECIPIENTS

Interferon treatment of hepatitis C virus (HCV) infection in transplant recipients carries a high risk of rejection. We treated these patients with ultralow-dose interferon-&agr; (1×106 units subcutaneously three times/week) plus ribavirin (600 mg/day) for 48 weeks. Treatment efficacy was evaluated by the changes of serum liver enzymes and viral load. A total of 11 patients were recruited for the study; biochemical response was obtained in all patients but one. Three patients terminated the therapy prematurely because of acute graft failure (one case) and urosepsis (two cases). Of the eight patients who completed a full course of therapy, five cleared HCV RNA at the end of treatment. Sustained biochemical and virologic responses were obtained in three patients (37.5%). Our regimen seemed to be relatively safe for renal transplant recipients with HCV. A significant portion of patients may achieve sustained biochemical and virologic responses.
Vision-based lane detection and tracking for driver assistance systems: A survey

Lane detection and tracking has been an active research area in the past twenty years mainly for the driver assistance application. Due to the large variations of traffic scenes and illumination conditions, this problem causes the usage of diverse approaches and sensing modalities. In this paper, we review the vision-based lane detection and tracking methods complemented with other sensor information when necessary. Approaches that adopt conventional computer vision techniques are reviewed and compared according to the separate functional modules in a generic framework. The recently developed machine learning especially deep learning based methods in the limited literature are analysed and also discussed, demonstrating high potential in the current and future challenging lane perception scenarios. While impressive achievements have been demonstrated under limited scenarios, new ideas and approaches are still desired such that the next generation robust and efficient system can be built in the service of autonomous vehicles.
Reliability of studies of iodine intake and recommendations for number of samples in groups and in individuals

The iodine intake level in a population is determined in cross-sectional studies. Urinary iodine varies considerably and the reliability of studies of iodine nutrition and the number of samples needed is unsettled. We performed a longitudinal study of sixteen healthy men living in an area of mild to moderate iodine deficiency. Iodine and creatinine concentrations were measured in spot urine samples collected monthly for 13 months. From these data we calculated the number of urine samples needed to determine the iodine excretion level for crude urinary iodine and for 24 h iodine excretion estimated from age- and gender-specific creatinine excretions. We found that mean urinary iodine excretion varied from 30 to 87 μg/l (31 to 91 μg/24 h). Sample iodine varied from 10 to 260 μg/l (20 to 161 μg/24 h). Crude urinary iodine varied more than estimated 24 h iodine excretion (population standard deviation 32 v. 26; individual standard deviation 29 v. 21; Bartlett's test, P < 0·01 for both). The number of spot urine samples needed to estimate the iodine level in a population with 95 % confidence within a precision range of ± 10 % was about 125 (100 when using estimated 24 h iodine excretions), and within a precision range of ± 5 % was about 500 (400). A precision range of ± 20 % in an individual required twelve urine samples or more (seven when using estimated 24 h iodine excretions). In conclusion, estimating population iodine excretion requires 100–500 spot urine samples for each group or subgroup. Less than ten urine samples in an individual may be misleading.
Immunohistochemical analysis of Fas and FLIP in prostate cancers

Fas‐mediated apoptosis is considered a principal pathway for apoptosis induction in normal and cancer cells. Expression of Fas has been reported in prostate tissues several times, but the data were not consistent. Expression of FLICE‐like inhibitory protein (FLIP), an inhibitor of Fas‐mediated apoptosis, has not been studied by immunohistochemistry in prostate tissues. The aim of this study is to explore whether alterations of Fas and FLIP expression occur in prostate cancer tissues. We analyzed the expression of Fas and FLIP in 107 prostate adenocarcinoma tissues by immunohistochemistry using a tissue microarray approach. Normal glandular cells of the prostates strongly expressed both Fas and FLIP proteins. Prostate intraepithelial neoplasm also showed a strong Fas immunoreacitity. Fas expression was strongly positive in 60 cancers (56.1%), but the remaining 47 cancers showed no (6.5%) or markedly decreased (37.4%) Fas immunostaining compared with the normal glandular cells of the same patients. By contrast, FLIP expression was strong in most (103/107; 96.3%) of the cancers, and only four cancers (3.7%) showed decreased immunoreactivities compared with the normal cells. The decreased expression of Fas was not associated with pathologic characteristics, including FLIP expression, size of the cancers, age, Gleason score and stage. The decreased expression of Fas in a large fraction of prostate cancers compared with their normal cells suggested that loss of Fas expression might play a role in tumorigenesis in some prostate cancers possibly by inhibiting apoptosis mediated by Fas.
Grb10 Interacts Differentially with the Insulin Receptor, Insulin-like Growth Factor I Receptor, and Epidermal Growth Factor Receptor via the Grb10 Src Homology 2 (SH2) Domain and a Second Novel Domain Located between the Pleckstrin Homology and SH2 Domains*

The Grb10 protein appears to be an adapter protein of unknown function that has been implicated in insulin receptor (IR) signaling. The interaction of this protein with the IR has been shown to be mediated in part by the Src homology 2 (SH2) domain of Grb10. Here we demonstrate the existence of a second novel domain within Grb10 that interacts with the IR and insulin-like growth factor receptor in a kinase-dependent manner. This domain was localized to a region of approximately 50 amino acids, and we term it the BPS domain to denote its location between thePH and SH2 domains. The BPS domain does not bear any obvious resemblance to other known protein interaction domains but is highly conserved among the Grb10-related proteins Grb7 and Grb14. We show that the BPS domain interaction is dependent upon receptor tyrosine kinase activity. Furthermore, interaction of the BPS domain requires the kinase domain of the IR, since mutation of the paired tyrosine residues (Y1150F/Y1151F) within the IR activation loop dramatically reduced the interaction. Last, our data suggest that the presence of two distinct protein interaction domains may help to determine the specificity by which Grb10 interacts with different receptors. Specifically, the IR, which appears to interact most strongly with Grb10, interacts well with both the SH2 and BPS domains. Conversely, the insulin-like growth factor receptor and EGFR, which interact less avidly with Grb10, interact well only with the BPS domain or the SH2 domain, respectively. In summary, our findings demonstrate the existence of a previously unidentified tyrosine kinase activity-dependent binding domain located between the Pleckstrin homology and SH2 domains of Grb10.
Regional benefits of servitization processes: evidence from the wind-to-energy industry

ABSTRACT By studying servitization processes and service competencies in the wind-to-energy industry in European regions, this paper provides a framework for territorial servitization. The framework resonates with the concepts of knowledge-intensive business services (KIBS) and industry life cycles, and its elements can be embedded into concepts of regional development (e.g., lead-market models, sustainability transitions, territorial innovation models). The framework suggests that regions benefit from servitization processes via the interplay of generating employment opportunities, enabling an efficient allocation of technology resources, opening up new markets, strengthening territorial competitiveness, raising the odds of securing employment in the consolidation period and enabling technological leaps.
CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non‐small cell lung cancer

Aberrant promoter methylation of the checkpoint gene with forkhead‐associated domain and ring finger (CHFR) gene is frequently detected in human cancer. We previously demonstrated that diminished CHFR expression was significantly correlated with both poor prognosis and heavy smoking in nonsmall cell lung cancer (NSCLC). Conversely, epidermal growth receptor (EGFR) mutation is detected in NSCLC among those who have never smoked or smoked lightly. To address the frequency of CHFR hypermethylation as well as differences in the distributions and clinicopathologic backgrounds against EGFR mutation in NSCLC, we investigated a large group of 208 NSCLC patients, including 165 with adenocarcinoma (ADC), 40 with squamous cell carcinoma and three others. We found that CHFR hypermethylation and EGFR mutation are mutually exclusive and have contrastive clinicopathologic backgrounds in NSCLC. Methylation‐specific polymerase chain reaction (MSP) and direct DNA sequencing were performed to detect CHFR hypermethylation and EGFR mutation, respectively. CHFR hypermethylation was found in 29 cases (14%) (16 ADC (8%), 12 SCC (6%) and one adenosquamous carcinoma), while EGFR mutation was detected in 48 (23%) cases, all of which were ADC. CHFR hypermethylation and EGFR mutation were mutually exclusive (p = 0.004). NSCLC with altered CHFR was significantly correlated with smoking history, poor differentiation, lymphatic invasion, and poor prognosis; this contrasted sharply with EGFR mutation, which had statistically better clinical outcomes. Our results demonstrate that CHFR loss might be critical for the tumorigenesis of NSCLC in patients with a history of smoking and induces tumors of a more malignant phenotype than the EGFR mutation. Thus, CHFR alteration should be considered a therapeutic target against NSCLC in patients with poor prognoses.
Simultaneous Cell-to-Cell Transmission of Human Immunodeficiency Virus to Multiple Targets through Polysynapses

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) efficiently propagates through cell-to-cell contacts, which include virological synapses (VS), filopodia, and nanotubes. Here, we quantified and characterized further these diverse modes of contact in lymphocytes. We report that viral transmission mainly occurs across VS and through “polysynapses,” a rosette-like structure formed between one infected cell and multiple adjacent recipients. Polysynapses are characterized by simultaneous HIV clustering and transfer at multiple membrane regions. HIV Gag proteins often adopt a ring-like supramolecular organization at sites of intercellular contacts and colocalize with CD63 tetraspanin and raft components GM1, Thy-1, and CD59. In donor cells engaged in polysynapses, there is no preferential accumulation of Gag proteins at contact sites facing the microtubule organizing center. The LFA-1 adhesion molecule, known to facilitate viral replication, enhances formation of polysynapses. Altogether, our results reveal an underestimated mode of viral transfer through polysynapses. In HIV-infected individuals, these structures, by promoting concomitant infection of multiple targets in the vicinity of infected cells, may facilitate exponential viral growth and escape from immune responses.
Heterologous Production of Hyaluronic Acid in an ε-Poly-l-Lysine Producer, Streptomyces albulus

ABSTRACT Hyaluronic acid (HA) is used in a wide range of medical applications, where its performance and therapeutic efficacy are highly dependent on its molecular weight. In the microbial production of HA, it has been suggested that a high level of intracellular ATP enhances the productivity and molecular weight of HA. Here, we report on heterologous HA production in an ε-poly-l-lysine producer, Streptomyces albulus, which has the potential to generate ATP at high level. The hasA gene from Streptococcus zooepidemicus, which encodes HA synthase, was refactored and expressed under the control of a late-log growth phase-operating promoter. The expression of the refactored hasA gene, along with genes coding for UDP-glucose dehydrogenase, UDP-N-acetylglucosamine pyrophosphorylase, and UDP-glucose pyrophosphorylase, which are involved in HA precursor sugar biosynthesis, resulted in efficient production of HA in the 2.0 MDa range, which is greater than typical bacterial HA, demonstrating that a sufficient amount of ATP was provided to support the biosynthesis of the precursor sugars, which in turn promoted HA production. In addition, unlike in the case of streptococcal HA, S. albulus-derived HA was not cell associated. Based on these findings, our heterologous production system appears to have several advantages for practical HA production. We propose that the present system could be applicable to the heterologous production of a wide variety of molecules other than HA in the case their biosynthesis pathways require ATP in vivo.
ASSESSMENT OF ENTREPRENEURSHIP EDUCATION TRENDS IN THE FORMAL EDUCATION SYSTEM IN TANZANIA

This article aims to assess the trend of entrepreneurial education within the formal education system through reflecting on the link between the national strategies and practice in Tanzanian formal education curricular. The article adopted the Fayolle’s teaching model for entrepreneurship education, focusing on the ontological and educational levels. Methodologically, the Tanzanian framework for entrepreneurship training has been analysed along with some national policies and curricular. Theoretical and empirical literature has also been systematically reviewed. Analysis of reviewed documents indicates a variation in the terms of the extent in which entrepreneurial education has been incorporated in different levels and kinds of formal education system. While there are noticeable initiatives to promote entrepreneurial education in higher education, primary and secondary levels entrepreneurial education strategies have been minimal in practice. The article concludes that the Tanzanian framework for entrepreneurship education is a useful guide but it has not been reflected in the holistic formal education curricula. However, there are noticeable strategies in higher education, vocational education and teacher training institutions. The article is limited in terms of scope of empirical cases in different levels of education.
Imaging spatial learning in the brain using immediate early genes: insights, opportunities and limitations

Abstract Immediate early gene (IEG) imaging offers a sophisticated approach to study the neural basis of learning in the brain. Demonstrating a high degree of spatial resolution, the activation of entire neuronal ensembles at multiple time-points can be observed. IEG imaging techniques have revealed a high level of responsiveness to spatial exploration within the hippocampus and other brain regions. The pattern of IEG activation is tightly linked with specific environments and appears to be involved in the subsequent consolidation of spatial information. This incidental learning is a potential confounding factor in studies investigating the neural correlates of spatial learning in both the radial arm maze and water maze. Although both these tasks increase hippocampal IEG expression from baseline levels, where control groups have fully explored the apparatus in the absence of task demands, or where animals are performing a non-spatial task, IEG expression in this region is comparable to spatially trained groups. However, the relationship between IEG expression and task performance, as well as the pattern of brain activation has been shown to differentiate between experimental and control groups. Inconsistencies between training protocols appear to contribute to the discrepancies between reported findings, and the role of IEG expression in the retention of spatial memory tasks remains unclear. Further investigation of the time course and dynamics of IEG expression during learning and retention is required to fully interpret observed results.
Transaction cost optimization for online portfolio selection

To improve existing online portfolio selection strategies in the case of non-zero transaction costs, we propose a novel framework named Transaction Cost Optimization (TCO). The TCO framework incorporates the L1 norm of the difference between two consecutive allocations together with the principles of maximizing expected log return. We further solve the formulation via convex optimization, and obtain two closed-form portfolio update formulas, which follow the same principle as Proportional Portfolio Rebalancing (PPR) in industry. We empirically evaluate the proposed framework using four commonly used data-sets. Although these data-sets do not consider delisted firms and are thus subject to survival bias, empirical evaluations show that the proposed TCO framework may effectively handle reasonable transaction costs and improve existing strategies in the case of non-zero transaction costs.
S‐adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl‐xS

S‐adenosylmethionine (SAMe) and its metabolite 5′‐methylthioadenosine (MTA) are proapoptotic in HepG2 cells. In microarray studies, we found SAMe treatment induced Bcl‐x expression. Bcl‐x is alternatively spliced to produce two distinct mRNAs and proteins, Bcl‐xL and Bcl‐xS. Bcl‐xL is antiapoptotic, while Bcl‐xS is proapoptotic. In this study we showed that SAMe and MTA selectively induced Bcl‐xS in a time‐ and dose‐dependent manner in HepG2 cells. There are three transcription start sites in the human Bcl‐x gene which yield only Bcl‐xL in control HepG2 cells. SAMe and MTA treatment did not affect promoter usage, but while one promoter yielded only Bcl‐xL, the other two yielded both Bcl‐xL and Bcl‐xS, with Bcl‐xS as the predominant messenger RNA (mRNA) species. Trichostatin A, 3‐deaza‐adenosine, cycloleucine, and okadaic acid had no effect on Bcl‐xS induction by SAMe or MTA. Calyculin A and tautomycin, on the other hand, blocked SAMe and MTA‐mediated Bcl‐xS induction and apoptosis in a dose‐dependent manner. SAMe and MTA increased protein phosphatase 1 (PP1) catalytic subunit mRNA and protein levels and dephosphorylation of serine–arginine proteins, with the latter blocked by calyculin A. The effects of SAMe and MTA on Bcl‐xS, PP1 expression, and apoptosis were also seen in 293 cells, but not in primary hepatocytes. Induction of Bcl‐xS by ceramide in HepG2 cells also resulted in apoptosis. In conclusion, we have uncovered a highly novel action of SAMe and MTA, namely the ability to affect the cellular phosphorylation state and alternative splicing of genes, in this case resulting in the induction of Bcl‐xS leading to apoptosis. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2004;40:221–231.)
Liquid chromatography-tandem mass spectrometry determination of oxalate in spot urine

Abstract Background. For assessment of total oxalic acid (OX) status, reliable quantification of OX in both urine and plasma is important. For urine, but not plasma, a commercial kit is available. We have recently described a LC-MSMS method for OX in plasma. The aim of the present study was to evaluate the usefulness of this assay for urine. We also wanted to evaluate if 24 h urine collection could be substituted by OX/creatinine-ratio (U-OX/crea) in spot-urine, and establish precursory reference intervals for U-OX/crea in children and adults. Methods. Acidified urines were analysed and relevant validation parameters assessed. Diurnal excretion patterns were investigated in nine healthy volunteers on self-chosen diets. For method comparison, 29 urine samples were analysed with both the present method and a commercial urine-oxalate kit. Precursory reference values for U-OX/crea in children and adults (N=103, 1 month-76 years) were calculated. Results. The within-batch coefficient of variation (CV) was 2.5% and a relative recovery of 97% in urine spiked with 5–200 μmol/L OX was found. The LC-MSMS method gave 7.9% higher OX values compared to the kit. No significant diurnal pattern of U-OX/crea was observed. U-OX/crea in children decreases with age, with no gender dependency. In adults no age variation was found, but females had somewhat higher U-OX/Crea compared to males. Conclusion. The LC-MSMS method has proven useful for urinary OX quantification. Random spot-urine samples can be used. Age-dependent reference limits for U-OX/crea must be applied in children, in contrast to adults.