Miracle-dz/UniFAR-FTUs huggingface dataset:
Acetylcholine and acetyl‐CoA metabolism in differentiating SN56 septal cell line

The rate of acetylcholine (ACh) synthesis was found to depend on the activity of choline acetyltransferase (ChAT) and on the concentrations of the two substrates of this enzyme, choline and acetyl‐CoA. In SN56 cells treated for 3 days with 1 mM dbcAMP activities of ChAT and acetylcholinesterase (AChE) were elevated. It was accompanied by an increased activity of ATP‐citrate lyase (ACL)—an enzyme responsible for provision of part of acetyl‐CoA for ACh synthesis in cholinergic neurons. In contrast lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) activities were reduced by dbcAMP. Treatment with 0.001 mM all‐trans retinoic acid (RA) elevated ChAT and LDH activities but reduced the activities of AChE and ACL. The combined treatment with dbcAMP and tRA increased ChAT activity in supra‐additive fashion. The effects of these two compounds on the other enzymes were not additive. Neither compound altered the activities of carnitine acetyltransferase, acetyl‐CoA synthase, or acetyl‐CoA hydrolase. On the other hand, they decreased acetyl‐CoA content and rate of ACh release. Overall, the results indicate that tRA upregulates only ChAT expression, whereas dbcAMP upregulates several features of cholinergic neurons including ChAT, AChE, and ACL. Low levels of acetyl‐CoA in differentiated cells may result in a low rate of ACh release and resynthesis during their depolarization. J. Neurosci. Res. 57:131–136, 1999. © 1999 Wiley‐Liss, Inc.
Epistemic Rhetorical Stance: Hedges and Boosters in L1 and L2 Students` English Writing

A key aspect of academic writing involves delivering writer`s argument with an appropriate degree of mitigated expression and strong assertion. However, positioning statements with balanced qualification and certainty remains a formidable challenge for second language learners. Despite its significance, we know little on the use of epistemic devices in Korean students` English writing. The purpose of this paper is to compare the expression of doubt and certainty in English writing by Korean students to those of native speakers based on the learners corpora. The results indicate that Korean learners take a stronger stance in their statements, relying on a narrower range of lexical items with simpler constructions, compared to their British counterparts. Importantly, a detailed analysis regarding the language proficiency reveals that usages of epistemic metadiscourse markers in L2 essays are strongly related to the proficiency levels. Lower ability bands exhibit a heavy reliance on limited items with strong assertions while higher proficiency bands prefer alleviated expressions rather than strong assertions by employing more hedges, representing balanced distributions across lexical items.
On the Effects of Geometry Control on the Performance of Overtopping Wave Energy Converters

Overtopping wave energy converters (OWECs) are designed to extract energy from ocean waves based on wave overtopping into a reservoir, which is emptied into the ocean through a set of low-head turbines, and typically feature a low crest freeboard and a smooth impermeable steep slope. In the process of optimizing the performance of OWECs, the question arises whether adapting the slope geometry to the variable wave characteristics at the deployment site (i.e., geometry control) can increase the overall hydraulic efficiency and overall hydraulic power compared to a fixed slope geometry. The effect of five different geometry control scenarios on the overall hydraulic efficiency and overall hydraulic power of OWECs has been simulated for three possible deployment sites using empirical prediction formulae. The results show that the effect of an adaptive slope angle is relatively small. On the other hand, adapting the crest freeboard of the OWECs to the wave characteristics increases the overall hydraulic efficiency and power. Based on the simulations, gains in overall hydraulic power of at least 30% are achievable when applying an adaptive crest freeboard compared to a fixed crest freeboard.
Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients.

AIMS The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics. METHODS The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring. RESULTS A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 +/- 0.2 l h(-1). Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 +/- 0.5 days, with a maximal value of 5.6 l h(-1). Moreover clearance increased by approximately 1.6 fold (range 0.5-1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 +/- 13 l kg(-1)) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F. CONCLUSIONS The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.
Phase I Dose-Escalation Study of the Pan-HER Inhibitor, PF299804, in Patients with Advanced Malignant Solid Tumors

Purpose: PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies. Experimental Design: PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non–small cell lung cancer (NSCLC) patients. Results: 121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/d. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non–small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804. Conclusions: The MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients. Clin Cancer Res; 17(5); 1131–9. ©2011 AACR.
Acute Bronchospasm from the Patient's Perspective: Role of Patient Education

Patient education is a vital tool for managing patients with acute broncho‐spasm arising from both asthma and chronic obstructive pulmonary disease (COPD). Both are serious chronic diseases, and lack of patient education usually results in lack of patients' adherence to their therapies. Several surveys indicate that a tremendous disparity exists between physicians and patients with asthma in how they perceive control of the patient's lung disease. A high proportion of physicians report that they provide patient education, and a low proportion of patients claim to have received adequate education. Management plans for both asthma and COPD are outlined, including instructions for the use of peak‐flow meters and profiles of inhalation devices. Although inhalation devices will continue to be the most common delivery systems for airway diseases that cause acute bronchospasm, their proper use can be both complex and diverse. Patient education, therefore, is essential for optimal benefit from therapy.
Competing Identities: A Field Study of In�?Group Bias Among Professional Evaluators

I use data from the Olympic sport of dressage to explore in‐group biases among judges. Dressage – the only international sport with subjective performance evaluations in which men and women compete as equals – provides a rare opportunity to identify multiple in‐group biases in the same naturally occurring setting. While, on average, judges are not biased in favour of either gender, they exhibit substantial biases in favour of (i) athletes of their own nationality, and (ii) athletes of the same nationality as the other judges in the competition. Heterogeneity across competitions suggests that biases increase as group identity becomes more salient.
Analyzing the level of knowledge and attitude of the mothers referring the urban health centers of Birjand about nutritional behaviors

Background: Achieving a balanced and proper nutrition is one of the most important health objectives in the early years of the child's life. The aim of this study is to determine the level of knowledge and attitude of the mothers covered by the urban health centers of Birjand about nutritional behaviors. Materials and Methods: This descriptive-analytical study was conducted on the mothers with children less than five years referring the health centers of Birjand, in 1387. A questionnaire was prepared for data collection. Data were analyzed using SPSS software, Chi square, ANOVA, Tukey's post hoc and Pearson correlation coefficient statistical tests with a accuracy level of P < 0.05. Results: Two hundred ninety four patients were studied. A meaningful difference was observed between the knowledge and attitude scores in terms of the mothers’ education stand (P = 0.002). Eighty three point seven percent, 65.6%, 82.7% and 64.6% of mothers were aware about the importance of iron absorption, the onset of iron supplement drop, the minerals and vitamins in the body, and the effects of vitamin A deficiency, respectively. The mothers’ knowledge and attitude about the nutritional behavior was evaluated at the average and good level, respectively. Conclusions: Considering the average level of the mothers’ knowledge and attitude about children's nutritional behaviors, the retraining of family physicians and health centers staff about the importance of nutritional behaviors is recommended.
Myeloid-Derived Suppressor Cells Predict Survival of Patients with Advanced Melanoma: Comparison with Regulatory T Cells and NY-ESO-1- or Melan-A–Specific T Cells

Purpose: To analyze the prognostic relevance and relative impact of circulating myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) compared with functional tumor antigen–specific T cells in patients with melanoma with distant metastasis. Experimental Design: The percentage of CD14+CD11b+HLA-DR−/low MDSCs, CD4+CD25+FoxP3+ Tregs, and the presence of NY-ESO-1- or Melan-A–specific T cells was analyzed in 94 patients and validated in an additional cohort of 39 patients by flow cytometry. Univariate survival differences were calculated according to Kaplan–Meier and log-rank tests. Multivariate analyses were performed using Cox regression models. Results: NY-ESO-1–specific T cells, the M-category, and the frequency of MDSCs were associated with survival. The absence of NY-ESO-1–specific T cells and the M-category M1c independently increased the risk of death. In a second Cox model not considering results on antigen-specific T cells, a frequency of >11% MDSCs showed independent impact. Its association with survival was confirmed in the additional patient cohort. Median survival of patients with a lower frequency of MDSCs was 13 months versus 8 months for others (P < 0.001, combined cohorts). We observed a strong correlation between high levels of MDSCs and the absence of melanoma antigen–specific T cells implying a causal and clinically relevant interaction. No prognostic impact was observed for Tregs. Conclusions: Circulating CD14+CD11b+HLA-DR−/low MDSCs have a negative impact on survival and inversely correlate with the presence of functional antigen–specific T cells in patients with advanced melanoma. Our findings provide a rationale to investigate MDSC-depleting strategies in the therapeutic setting especially in combination with vaccination or T-cell transfer approaches. Clin Cancer Res; 20(6); 1601–9. ©2013 AACR.
Histological characteristics of metastasizing thin melanomas: a case-control study of 43 cases.

OBJECTIVE To study clinical and histological features associated with metastasizing thin melanomas (MTMs). DESIGN Case-control study of clinicopathological features of patients with MTMs by a panel of 10 dermatopathologists. SETTING Members of the North American Melanoma Pathology Study Group selected the cases from the melanoma databases at 8 academic institutions. PATIENTS Forty-three patients with MTMs (<1 mm thick) and 42 control subjects without metastasis matched for age, sex, tumor site, and Breslow thickness. INTERVENTION None. MAIN OUTCOME MEASURES Clinical (age, sex, site of lesion, stage at diagnosis, metastasis site, disease-free survival, and outcome) and histological (Breslow thickness, Clark level, growth phase, regression, and inflammatory response) features of patients with MTMs vs controls. RESULTS There was an overrepresentation of axial tumors among patients with MTMs. Extensive regression was present in 18 patients (42%) with MTM vs 2 matched control subjects (5%) (95% confidence interval, 21%-53%; P =.001). Other histological variables were not significantly different. Two patients had melanomas in situ with subsequent metastasis. CONCLUSIONS Thin melanomas with extensive regression represent a group at higher risk for the development of metastasis. Furthermore, the risk of metastasis cannot be dismissed in cases of melanoma in situ.
Through Her Eyes

A major component of a woman's ability to resist assaults by strangers versus acquaintances lies in the social and cognitive context in which she is engaged with the perpetrator and within which she must recognize potential threat before engaging in a behavioral response. This paper presents questionnaire and focus group findings of heterosexual college sorority women's social contexts, perceived risks, responses, and psychological barriers to protecting themselves from sexual aggression threat by fraternity acquaintances. Several social and cognitive factors, including alcohol consumption and psychological barriers, were related to projected responses to sexual aggression. Participants in general held a high sense of invulnerability to victimization and an optimistic belief in their ability to resist sexual aggression. Several differences between previously victimized and nonvictimized women also emerged.
Ketamine and Remifentanil Interactions on the Sevoflurane Minimum Alveolar Concentration and Acute Opioid Tolerance in the Rat

BACKGROUND: Ketamine is used at low doses for its analgesic and antihyperalgesic properties when combined with opioids but also when opioid-induced hyperalgesia and tolerance appear. In this study we determined the interaction of ketamine and remifentanil on the minimum alveolar concentration (MAC) of sevoflurane in rats and to determine whether ketamine may block acute opioid tolerance (AOT). METHODS: Male Wistar rats were anesthetized with sevoflurane, and the MAC was determined before and after ketamine administration (10, 20, 40, and 80 mg kg−1 or saline) alone or combined with remifentanil (120 and 240 &mgr;g kg−1 h−1, low and high doses, respectively). One additional group received the lowest ketamine dose after starting a remifentanil infusion. Finally, naloxone was administered to determine the potential action of ketamine on opioid receptors. MAC was determined from intratracheal gas samples, and tail clamping was used as a supramaximal stimulus. End-tidal anesthetic concentrations were assayed using a side stream gas analyzer. Statistical analysis was performed with an analysis of variance. RESULTS: Ketamine and remifentanil dose-dependently reduced the MAC. Adding the low dose of remifentanil to ketamine did not improve the MAC reduction, whereas the high dose of remifentanil enhanced ketamine reduction in a subadditive fashion. Nevertheless, ketamine was unable to block the development of AOT to remifentanil at either dose. Finally, naloxone blocked the MAC reduction produced by ketamine. CONCLUSIONS: A subadditive effect between ketamine and remifentanil was found on the sevoflurane MAC reduction rats. In addition, ketamine was unable to block AOT. The clinical relevance of these findings should be elucidated in future studies to reduce anesthetic requirements.
Nitric oxide does not modulate whole body oxygen consumption in anesthetized dogs.

The effects of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and the NO donor sodium nitroprusside (SNP) on whole body O2 consumption (VO2) were assessed in 16 dogs anesthetized with fentanyl or isoflurane. Cardiac output (CO) and mean arterial pressure (MAP) were measured with standard methods and were used to calculate VO2 and systemic vascular resistance (SVR). Data were obtained in each dog under the following conditions: 1) Control 1, 2) SNP (30 microg. kg-1. min-1 iv) 3) Control 2, 4) L-NAME (10 mg/kg iv), and 5) SNP and adenosine (30 and 600 microg. kg-1. min-1 iv, respectively) after L-NAME. SNP reduced MAP by 29 +/- 3% and SVR by 47 +/- 3%, while it increased CO by 39 +/- 9%. L-NAME had opposite effects; it increased MAP and SVR by 24 +/- 4% and 103 +/- 11%, respectively, and it decreased CO by 37 +/- 3%. Neither agent changed VO2 from the baseline value of 4.3 +/- 0.2 ml. min-1. kg-1, since the changes in CO were offset by changes in the arteriovenous O2 difference. Both SNP and adenosine returned CO to pre-L-NAME values, but VO2 was unaffected. We conclude that 1) basally released endogenous NO had a tonic systemic vasodilator effect, but it had no influence on VO2; 2) SNP did not alter VO2 before or after inhibition of endogenous NO production; 3) the inability of L-NAME to increase VO2 was not because CO, i.e., O2 supply, was reduced below the critical level.
Prevention of pancreatic cancer induction in hamsters by metformin.

BACKGROUND AND AIMS Our previous study suggested that the known promotional effect of a high fat diet, which in hamsters induces peripheral insulin resistance, is related to a compensatory proliferation of islet cells. The present study was to examine whether the prevention of islet cell proliferation can inhibit the promotional effect of a high-fat diet in pancreatic carcinogenesis. METHODS Two groups of high fat-fed hamsters were used. One group received Metformin in drinking water for life (HF+Met group), and the other group served as a control (HF group). At the time when the normalization of the plasma insulin level was expected, all hamsters were treated with the pancreatic carcinogen, N-nitrosobis-(2-oxopropyl)amine, and the experiment was terminated 42 weeks later. RESULTS Although 50% of the hamsters in the high-fat group developed malignant lesions, none was found in the HF+Met group (P < 0.05). Also, significantly more hyperplastic and premalignant lesions, most of which were found within the islets, were detected in the high-fat group (8.6 lesions/hamster) than in the HF+Met group (1.8 lesions/hamster). CONCLUSIONS The results lend further support on the significant role of islet cells in pancreatic carcinogenesis and may explain the association between pancreatic cancer and obesity, which is usually associated with peripheral insulin resistance.
Mechanism of Action at the Molecular Level of the Antiviral Drug 3(2H)-Isoflavene against Type 2 Poliovirus

ABSTRACT The mechanism of action of the antiviral compound 3(2H)-isoflavene against Sabin type 2 poliovirus has been studied, and interference with virus uncoating was demonstrated. Isolation and sequencing of drug-resistant variants revealed single amino acid substitutions (I194M or D131V) in the VP1 capsid protein. While M194 is located in a hydrophobic pocket and should partially fill the space occupied by the isoflavene ring, V131 is exposed on the VP1 surface, forming a contact with VP4. The D131V mutation most likely induces local conformational changes in VP1 and/or VP4 that affect viral flexibility. Two dependent variants, N53S of VP1 and K58E of VP4, both located on the inner surface of the capsid, near the threefold axis of symmetry, were also selected. Both mutations affected viral stability, allowing the transition to 135S particles in the absence of drug, without the involvement of the viral receptor.
Concordant Modulation of Neutralization Resistance and High Infectivity of the Primary Human Immunodeficiency Virus Type 1 MN Strain and Definition of a Potential gp41 Binding Site in gp120

ABSTRACT Efforts to develop a vaccine against human immunodeficiency virus type 1 (HIV-1) are complicated by resistance of virus to neutralization. The neutralization resistance phenotype of HIV-1 has been linked to high infectivity. We studied the mechanisms determining this phenotype using clones of the T-cell-line-adapted (TCLA) MN strain (MN-TCLA) and the neutralization-resistant, primary MN strain (MN-P). Mutations in the amino- and carboxy-terminal halves of gp120 and the carboxy terminus of gp41 contributed to the neutralization resistance, high-infectivity phenotype but depended upon sequences in the leucine zipper (LZ) domain of gp41. Among 23 clones constructed to map the contributing mutations, there was a very strong correlation between infectivity and neutralization resistance (R2 = 0.81; P < 0.0001). Mutations that distinguished the gp120s of MN-P and MN-TCLA clones were clustered in or near the CD4 and coreceptor binding sites and in regions distant from those binding sites. To test the hypothesis that some of these distant mutations may interact with gp41, we determined which of them contributed to high infectivity and whether those mutations modulated gp120-gp41 association in the context of MN-P LZ sequences. In one clone, six mutations in the amino terminus of gp120, at least four of which clustered closely on the inner domain, modulated infectivity. This clone had a gp120-gp41 association phenotype like MN-P: in comparison to MN-TCLA, spontaneous dissociation was low, and dissociation induced by soluble CD4 binding was high. These results identify a region of the gp120 inner domain that may be a binding site for gp41. Our studies clarify mechanisms of primary virus neutralization resistance.