Miracle-dz/UniFAR-FTUs huggingface dataset:
Specificity in transcriptional regulation in the absence of specific DNA binding sites: the case of T7 lysozyme.

The binding of T7 lysozyme to T7 RNAP increases the apparent Km for NTP during initiation (formation of the first phosphodiester bond). It also increases the dissociation constant and dissociation rate of product dinucleotide from the polymerase. Higher NTP concentrations are required for maximal rates of productive initiation from T7 class II versus class III promoters, though individual promoters display distinct responses to changes in NTP concentrations. The greater degree of repression of class II versus class III promoters by T7 lysozyme, which appears to be important for the switch to class III gene expression during the phage life cycle, might therefore be a consequence of: (1) T7 lysozyme generally reducing the affinity of the polymerase for NTPs and increasing the rate of release of transcripts, and (2), intrinsically higher NTP concentration requirements for productive initiation from class II promoters. T7 lysozyme is also found to inhibit the addition of untemplated bases to the transcript which can occur when the elongation complex reaches the end of a template, and its effects are qualitatively similar to those reported for mutations in the extreme C terminus of T7 RNAP. Together with the locations of polymerase mutations which cause resistance or hypersensitivity to T7 lysozyme, these observations suggest that the structural mechanism of lysozyme action might include conformational changes in the C-terminal loop (aa. approximately 820-883) of T7 RNAP.
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABAA receptor β3 subunit

General anesthetics are widely used in clinical practice. On the molecular level, these compounds have been shown to modulate the activity of various neuronal ion channels. However, the functional relevance of identified sites in mediating essential components of the general anesthetic state, such as immobility and hypnosis, is still unknown. Using gene‐targeting technology, we generated mice harboring a subtle point mutation (N265M) in the second transmembrane region of the β3 subunit of the GABAA receptor. In these mice, the suppression of noxious‐evoked movements in response to the intravenous anesthetics etomidate and propofol is completely abolished, while only slightly decreased with the volatile anesthetics enflurane and halothane. β3(N265M) mice also display a profound reduction in the loss of righting reflex duration in response to intravenous but not volatile anesthetics. In addition, electrophysiological recordings revealed that anesthetic agents were significantly less effective in enhancing GABAA receptor‐mediated currents, and in decreasing spontaneous action potential firing in cortical brain slices derived from mutant mice. Taken together, our results demonstrate that a single molecular target, and indeed a specific residue (N265) located within the GABAA receptor β3 subunit, is a major determinant of behavioral responses evoked by the intravenous anesthetics etomidate and propofol, whereas volatile anesthetics appear to act via a broader spectrum of molecular targets.
Endogenous prostaglandins in gastric alkaline response in the rat stomach after damage.

A role of endogenous prostaglandins in gastric alkaline response (an increase of luminal pH) and functional recovery was investigated in the rat stomach after damage with acidified taurocholate (TC, 20 mM) or aspirin (ASA, 40 mM). Exposure of the stomach to TC or ASA similarly produced a transmucosal potential difference (PD) reduction and enhancement of H+ backdiffusion. The PD was restored gradually with time, and this process was much faster in the case of TC compared with ASA. After exposure to TC, acid secretion ceased and bicarbonate (0.5-1 mu eq/10 min) appeared in the lumen, whereas acid secretion persisted in the stomach exposed to ASA. However, in the presence of cimetidine (8 mg . kg-1 . h-1), these two agents produced a similar degree of luminal alkalinization (approximately 1 mu eq/10 min of HCO3-). Pretreatment with indomethacin (5 mg/kg, sc) significantly inhibited luminal alkalinization and PD recovery seen after exposure to TC. Concurrent administration of 16,16-dimethyl prostaglandin E2 (3 micrograms/kg, sc) antagonized the effects of indomethacin in stomachs exposed to TC and also unmasked luminal alkalinization and expedited the PD recovery in stomachs exposed to ASA. The levels of PGE2 and 6-keto-PGF1 alpha in the corpus mucosa were significantly increased in stomachs exposed to TC, but decreased in those exposed to ASA. These results indicate that luminal alkalinization of the stomach after damage with TC results from both an inhibition of acid secretion caused by endogenous prostaglandins and an increased appearance of HCO-3, and may play a role in functional recovery of the damaged mucosa. Gastric alkalinization seems to be a common phenomenon after exposure to mucosal damaging agents unless they have an inhibitory effect on prostaglandin biosynthesis.
Zidovudine Phamacokinetics in Five HIV Seronegative Patients Undergoing Continuous Ambulatory Peritoneal Dialysis

A few reports in the literature describe zidovudine (AZT) pharmacokinetics in patients undergoing hemodialysis; however, the effect of continuous ambulatory peritoneal dialysis (CAPD) on the drug's disposition has not been studied. The pharmacokinetics of AZT were evaluated in five patients, age 37–62 years, who were seronegative for the human immunodeficiency virus and were undergoing CAPD. Serial plasma, urine, and dialysate samples were collected after oral administration of AZT 200 mg. Samples were assayed using radioimmunoassay (RIA). Model‐independent analysis was used to determine total plasma clearance, apparent volume of distribution, mean residence time, and half‐life. Net peritoneal dialysis clearance was calculated to measure the effect of CAPD on AZT disposition. We found wide interpatient variability in AZT pharmacokinetics. Peak serum concentrations ranged from 0.3–47.8 μm and area under the curve from 0.5–26.1 mg × hour/L. These differences resulted in corresponding differences in clearance (range 66–3176 ml/min/1.73 m2) and volume of distribution (range 16–825 L). Interpatient variability in glucuronidation may partially account for this variability. Net peritoneal dialysis clearance of AZT was 5 ml/minute. Although the effect of peritoneal dialysis on AZT disposition was negligible, clinicians should be aware of the large differences in the way in which individual patients with renal dysfunction handle this drug.
High‐resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well‐differentiated and dedifferentiated liposarcoma

Well‐differentiated liposarcoma (WDLS) is one of the most common malignant mesenchymal tumors and dedifferentiated liposarcoma (DDLS) is a malignant tumor consisting of both WDLS and a transformed nonlipogenic sarcomatous component. Cytogenetically, WDLS is characterized by the presence of ring or giant rod chromosomes containing several amplified genes, including MDM2, TSPAN31, CDK4, and others mainly derived from chromosome bands 12q13‐15. However, the 12q13‐15 amplicon is large and discontinuous. The focus of this study was to identify novel critical genes that are consistently amplified in primary (nonrecurrent) WDLS and with potential relevance for future targeted therapy. Using a high‐resolution (5.0 kb) “single nucleotide polymorphism”/copy number variation microarray to screen the whole genome in a series of primary WDLS, two consistently amplified areas were found on chromosome 12: one region containing the MDM2 and CPM genes, and another region containing the FRS2 gene. Based on these findings, we further validated FRS2 amplification in both WDLS and DDLS. Fluorescence in situ hybridization confirmed FRS2 amplification in all WDLS and DDLS tested (n = 57). Real time PCR showed FRS2 mRNA transcriptional upregulation in WDLS (n = 19) and DDLS (n = 13) but not in lipoma (n = 5) and normal fat (n = 9). Immunoblotting revealed high expression levels of phospho‐FRS2 at Y436 and slightly overexpression of total FRS2 protein in liposarcoma but not in normal fat or preadipocytes. Considering the critical role of FRS2 in mediating fibroblast growth factor receptor signaling, our findings indicate that FRS2 signaling should be further investigated as a potential therapeutic target for liposarcoma. © 2011 Wiley‐Liss, Inc.
Self-Reports of Psychosocial Functioning among Children and Young Adults with Cleft Lip and Palate

Objective: A cross-sectional study was employed to determine the psychosocial effects of cleft lip and/or palate among children and young adults, compared with a control group of children and young adults without cleft lip and palate. Participants: The study comprised 160 children and young adults with cleft lip and/or palate and 113 children and young adults without cleft lip and/or palate. All participants were between 8 and 21 years of age. Outcome measures: Psychological functioning (anxiety, self-esteem, depression, and behavioral problems) was assessed using validated psychological questionnaires. Happiness with facial appearance was rated using a visual analog scale. Social functioning, including experience of teasing/bullying and satisfaction with speech, was assessed using a semistructured interview. Results: Participants with cleft lip and/or palate reported greater behavioral problems (p < .001) and more symptoms of depression (p < .01); they were teased more often (p < .001) and were less happy with their facial appearance (p < .01) and speech (p < .001), compared with controls. There were no significant difference between subjects with cleft lip and/or palate and subjects without cleft lip and/or palate in terms of anxiety (p > .05) or self-esteem (p > .05). Having been teased was a significant predictor of poor psychological functioning, more so than having a cleft lip and/or palate per se (p < .001). Conclusions: Teasing was greater among participants who had cleft lip and/ or palate and it was a significant predictor of poorer psychosocial functioning. Children and young adults with cleft lip and/or palate require psychological assessment, specifically focusing on their experience of teasing, as part of their routine cleft care.
Diagnostic role of 18F-FDG PET/MRI in patients with gynecological malignancies of the pelvis: A systematic review and meta-analysis

Purpose The aim of this study was to assess the diagnostic performance of 18F-FDG Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) for gynecological cancers of the pelvis, based on a systematic review and meta-analysis of published data. Methods We performed a comprehensive literature search of Pubmed and Embase for studies that evaluated the diagnosis of 18F-FDG PET/MRI for gynecological malignancies in the pelvis. Quality Assessment for Studies of Diagnostic Accuracy 2 (QUADAS 2) tool was used to access the quality of included studies. After testing heterogeneity of the pooled studies with I^2 and H^2 (calculated using metaan in Stata12.0) we treated the data that extracted and transformation from the studies, based on DerSimonian-Laird method(Random-effects models),then back-transformation them to percentages and plotting to get the pooled sensitivity, specificity, likelihood ratios, and constructed summary receiver operating characteristics (SROC) curve. Results Eventually, 7 studies fulfilled our predefined inclusion criteria were included in our research. On patient-based assessment, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of 18F-FDG PET/MRI for diagnosis of gynecological malignancies were 0.95 (95%CI 0.86–0.99), 0.95 (95% CI 0.74–1.00), 7.51 (95% CI 2.29–24.59), 0.12 (95% CI 0.05–0.29) and 116.27 (95% CI 17.07–791.74), respectively. On lesion-based assessment, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and the summary DOR were 0.89 (95%CI 0.84–0.93), 0.87 (95%CI 0.74–0.95), 6.99 (95%CI 3.30–14.79), 0.12 (95%CI 0.06–0.25) and 55.82 (95%CI 20.91–149.05), respectively. Conclusions Our meta-analysis indicated that 18F-FDG PET/MRI, combined the advantages of MRI and PET, may be a very promising diagnostic method to assess the primary tumor and nodal staging in patients with gynecological malignancies of the pelvis.
Resorting to bilateralism: the EU, MERCOSUR, and the Strategic Partnership with Brazil

Abstract In 2007, the European Union (EU) launched a Strategic Partnership (SP) with Brazil despite its long-lasting interregional relationship with the Mercado Común del Sur (MERCOSUR). By singling out Brazil, the EU swung from the EU-MERCOSUR interregional negotiations on an Association Agreement (1999–2004) to bilateralism. In view of the EU’s increasing use of bilateralism, the article analyses why the EU shifted to this SP. Relying on elite interviews, it compares the interregional negotiations (1999–2004) with the bilateral talks with Brazil (since 2007). The EU switched venues from interregional to bilateral because it feared losing Brazil to its American and Chinese competitors. In Europe’s endeavour to prevent this loss, when interregional negotiations seemed fruitless because of MERCOSUR’s increasing fragmentation, the EU privileged Brazil as a strategic partner. Analysing this overlooked SP, the article looks at the – little studied – extra-regional factors that have rendered the EU’s commitment to regional integration vulnerable to bilateralism.
β-Elemene inhibits proliferation through crosstalk between glia maturation factor β and extracellular signal‑regulated kinase 1/2 and impairs drug resistance to temozolomide in glioblastoma cells.

β-elemene, a plant-derived drug extracted from Curcuma wenyujin, has demonstrated marked antiproliferative effects on glioblastoma, while toxicity remains low. However, the underlying molecular mechanisms of the antitumor activity of β-elemene remain to be elucidated. Previously, it was identified that the glia maturation factor β (GMFβ)/mitogen-activated protein kinase kinase (MAPK) 3/6/p38 pathway participates in the antiproliferative activity of β-elemene on glioblastoma. In the present study, in order to illustrate the association of GMFβ and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, U87 and U251 cells were treated with β-elemene at various doses and for different durations, and the expression of phosphorylated ERK1/2 (p-ERK1/2), ERK1/2, B-cell lymphoma 2 (Bcl-2), Bcl2-associated X and survivin was examined by western blot analysis. Following treatment with β-elemene and the ERK1/2 inhibitor PD98059, U87 cell viability was evaluated using a Cell Counting Kit-8 (CCK-8) assay, and the expression levels of Bcl-2 and survivin were examined by western blot analysis. GMFβ was then downregulated by RNA interference in β-elemene-treated U87 cells, and the effect of this on the expression of ERK1/2 and p-ERK1/2 was determined by western blot analysis. Finally, the chemosensitisation of U87 cells to temozolomide (TMZ) through β-elemene was examined using the CCK-8 assay. The results demonstrated that β-elemene inhibited the proliferation of U87 glioblastoma cells through the GMFβ‑dependent inactivation of the ERK1/2-Bcl-2/survivin pathway. Furthermore, inhibition of ERK1/2 by PD98059 enhanced the antitumor effect of β-elemene and impaired the expression levels of Bcl-2 and survivin. β-elemene also increased the sensitivity of U87 glioblastoma cells to the chemotherapeutic TMZ, which was synergistically enhanced by PD98059. In conclusion, these results suggested that GMFβ-dependent inactivation of the ERK1/2-Bcl-2/survivin pathway mediated the antiproliferative effect of β-elemene on glioblastoma. Therefore, β-elemene is a promising chemosensitizer or adjuvant therapeutic for TMZ against glioblastoma brain tumors.
EXPORTS AND ECONOMIC GROWTH: Further Evidence from Asian LDCs

Fueled by the adverse conditions in the current international economic environment, the debate concerning the relative merits of development strategies based on import-substitution or export-oriented policies, is starting anew. This paper re-estimates Federâ€™s (1982) model using data from fourteen Asian LDCs during 1965Â·1982 and finds that, although the social marginal factor productivities in the export sector declined significantly in the post-1973 period providing some support for the elasticity pessimism argument, they were, nevertheless, higher than in the nonÂ·export sector. This suggests that despite the deterioration of the international economy, reallocation of the export sector from the nonÂ·export sector could have increased growth rates.
Effect of aminophylline on recovery from sevoflurane anaesthesia.

BACKGROUND AND OBJECTIVE In this randomized, double-blind study, we aimed to investigate the effect of aminophylline on recovery from sevoflurane. METHODS One-hundred ASA I-II patients scheduled for elective surgery were randomly divided into two groups receiving either NaCl 0.9% (Group 1, n = 50) or aminophylline 5mg kg(-1) (Group 2, n = 50). All patients were premedicated with atropine 0.01 mgkg(-1) and midazolam 0.06mgkg(-1) intramuscularly. Anaesthesia was induced with propofol 2mg kg(-1) for muscle relaxation, and atracurium 0.5 mg kg(-1) was maintained with sevoflurane 2% in 50% oxygen and nitrous oxide. Further atracurium (0.1 mgkg(-1) was given when needed. Aminophylline or saline was given after sevoflurane was discontinued. Heart rate, mean arterial pressure, peripheral oxygen saturation, the duration of anaesthesia and recovery times (eye opening, verbal response, extubation and successful performance of arithmetical calculations) were recorded. RESULTS There were no statistically significant differences in mean arterial pressure, peripheral oxygen saturation and anaesthesia time between the two groups. Heart rate increased significantly (P < 0.05) after aminophylline and was also higher than in the placebo group. Recovery times were significantly shorter (P < 0.001) in the patients receiving aminophylline. CONCLUSIONS Aminophylline speeded recovery after sevoflurane anaesthesia and it may have some advantage in anaesthesia practice for patients.
Role of Putrescine on Androgen-Elicited Positive Inotropism in the Left Atrium of Rats

Functional and biochemical studies were performed in isolated left atria of male Wistar rats to study whether endogenous polyamines may mediate androgen-elicited positive inotropism and their relationship with a rise in cAMP during the cardiotonic effect. 5α-Dihydrotestosterone (100 μM) exposure increased intracellular putrescine as determined by HPLC, but it did not increase spermidine and spermine. This effect was antagonized by an inhibitor of ornithine decarboxylase, α-difluoromethylornithine (10 mM), suggesting enzyme activation. α-Difluoromethylornithine also antagonized androgens-elicited inotropism and the increase in intracellular cAMP. Putrescine (1 to 10 mM) elicited a concentration-dependent positive inotropism associated with the cAMP increase. The prior incubation with putrescine antagonized 5α-dihydrotestosterone-elicited inotropism and did not produce sinergism on intracellular cAMP. Short-term incubation with 5α-dihydrotestosterone or forskolin shifted to the left the cardiotonic effect of isoproterenol, an agonist of β-adrenoceptors, without any increase in Emax, suggesting that a common mechanism was involved. Therefore, polyamines might modulate the cAMP production associated with the cardiotonic effect of androgens.
Effects of pacing on stationary reentrant activity. Theoretical and experimental study.

It is well known that electrical pacing may either terminate or change the rate and/or ECG appearance of reentrant ventricular tachycardia. However, the dynamics of interaction of reentrant waves with waves initiated by external pacing are poorly understood. Prevailing concepts are based on simplistic models in which propagation occurs in one-dimensional rings of cardiac tissue. Since reentrant activation in the ventricles occurs in two or three dimensions, such concepts might be insufficient to explain the mechanisms of pacing-induced effects. We used numerical and biological models of cardiac excitation to explore the phenomena, which may take place as a result of electrical pacing during functionally determined reentry. Computer simulations of a two-dimensional array of electrically coupled FitzHugh-Nagumo cells were used to predict the response patterns expected from thin slices of sheep ventricular epicardial muscle, in which self-sustaining reentrant activity in the form of spiral waves was consistently initiated by premature stimulation and monitored by means of video mapping techniques. The results show that depending on their timing and shape, externally induced waves may collide with the self-sustaining spiral and result in one of three possible outcomes: (1) direct annihilation of the spiral, (2) multiplication of the spiral, or (3) shift of the spiral center (ie, core). Multiplication and shift of the spiral core were attended by changes in rate and morphology of the arrhythmia as seen by "pseudo-ECGs. " Furthermore, delayed termination (ie, termination of the activity one to three cycles after the stimulus) occurred after both multiplication and shift of the spiral center. Both numerical predictions and experimental results support the hypothesis that whether a pacing stimulus will terminate a reentrant arrhythmia or modify its ECG appearance depends on whether the interactions between the externally induced wave and the spiral wave result in the de novo formation of one or more "wavebreaks. " The final outcome depends on the stimulus parameters (ie, position and size of the electrodes and timing of the stimulus) as well as on the position of the newly formed wavebreak(s) in relation to that of the original wave.
In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials

The cyclin-dependent protein kinases are key regulators of cell cycle progression. Aberrant expression or altered activity of distinct cyclin-dependent kinase (CDK) complexes results in escape of cells from cell cycle control, leading to unrestricted cell proliferation. CDK inhibitors have the potential to induce cell cycle arrest and apoptosis in cancer cells, and identifying small-molecule CDK inhibitors has been a major focus in cancer research. Several CDK inhibitors are entering the clinic, the most recent being selective CDK2 and CDK4 inhibitors. We have identified a diaminopyrimidine compound, R547, which is a potent and selective ATP-competitive CDK inhibitor. In cell-free assays, R547 effectively inhibited CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D1 (Ki = 1–3 nmol/L) and was inactive (Ki > 5,000 nmol/L) against a panel of >120 unrelated kinases. In vitro, R547 effectively inhibited the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s ≤ 0.60 μmol/L. The growth-inhibitory activity is characterized by a cell cycle block at G1 and G2 phases and induction of apoptosis. R547 reduced phosphorylation of the cellular retinoblastoma protein at specific CDK phosphorylation sites at the same concentrations that induced cell cycle arrest, suggesting a potential pharmacodynamic marker for clinical use. In vivo, R547 showed antitumor activity in all of the models tested to date, including six human tumor xenografts and an orthotopic syngeneic rat model. R547 was efficacious with daily oral dosing as well as with once weekly i.v. dosing in established human tumor models and at the targeted efficacious exposures inhibited phosphorylation of the retinoblastoma protein in the tumors. The selective kinase inhibition profile and the preclinical antitumor activity of R547 suggest that it may be promising for development for use in the treatment of solid tumors. R547 is currently being evaluated in phase I clinical trials. [Mol Cancer Ther 2006;5(11):2644–58]