Miracle-dz/UniFAR-FTUs huggingface dataset:
Mycoplasma hyorhinis–Encoded Purine Nucleoside Phosphorylase: Kinetic Properties and Its Effect on the Cytostatic Potential of Purine-Based Anticancer Drugs

A mycoplasma-encoded purine nucleoside phosphorylase (designated PNPHyor) has been cloned and characterized for the first time. Efficient phosphorolysis of natural 6-oxopurine and 6-aminopurine nucleosides was observed, with adenosine the preferred natural substrate (Km = 61 µM). Several cytostatic purine nucleoside analogs proved to be susceptible to PNPHyor-mediated phosphorolysis, and a markedly decreased or increased cytostatic activity was observed in Mycoplasma hyorhinis–infected human breast carcinoma MCF-7 cell cultures (MCF-7.Hyor), depending on the properties of the released purine base. We demonstrated an ∼10-fold loss of cytostatic activity of cladribine in MCF-7.Hyor cells and observed a rapid and complete phosphorolysis of this drug when it was exposed to the supernatant of mycoplasma-infected cells. This conversion (inactivation) could be prevented by a specific PNP inhibitor. These findings correlated well with the high efficiency of PNPHyor-catalyzed phosphorolysis of cladribine to its less toxic base 2-chloroadenine (Km = 80 µM). In contrast, the cytostatic activity of nucleoside analogs carrying a highly toxic purine base and being a substrate for PNPHyor, but not human PNP, was substantially increased in MCF-7.Hyor cells (∼130-fold for fludarabine and ∼45-fold for 6-methylpurine-2′-deoxyriboside). Elimination of the mycoplasma from the tumor cell cultures or selective inhibition of PNPHyor by a PNP inhibitor restored the cytostatic activity of the purine-based nucleoside drugs. Since several studies suggest a high and preferential colonization or association of tumor tissue in cancer patients with different prokaryotes (including mycoplasmas), the data presented here may be of relevance for the optimization of purine nucleoside–based anticancer drug treatment.
Player and Team Performance in Everquest II and Halo 3

The market for video games has skyrocketed over the past decade. In the United States alone, the video game industry in 2009 generated almost US$20 billion in sales. Furthermore, according to Lenhart et al. (2008), an estimated 97% of the teenage population and 53% of the adult population are regular game players. Massively multiplayer online games (MMOGs) have become increasingly popular and amassed communities comprised of over 47 million subscribers by the year 2008. MMOGs are online spaces providing users with comprehensive virtual universes, each with its own unique context and mechanics. They range from the fantastical world of elves, dwarfs, and humans to space faring corporations and mirrors of our world. Large numbers of users interact and role-play via in-game mechanics.
Cystic and Adenofibromatous Clear Cell Carcinomas of the Ovary: Distinctive Tumors That Differ in Their Pathogenesis and Behavior: A Clinicopathologic Analysis of 122 Cases

Ovarian clear cell carcinomas (CCC) typically present as large adnexal, stage I tumors and are generally considered highly malignant. They are frequently associated with endometriosis and, less often with clear cell adenofibromas. We hypothesized that CCCs are a heterogeneous group of tumors, some arising from a cyst and others from an adenofibroma. To test this hypothesis, 122 cases of CCC were retrieved from the surgical pathology files of National Taiwan University Hospital (74), The Johns Hopkins Hospital (23), and Serei Mikatahara General Hospital (23) (1985 to 2006). Cases were divided into 3 subgroups: (1) cystic, (2) adenofibromatous, and (3) indeterminate. Various features were analyzed including: age, race, laterality, tumor size, architectural pattern (papillary, tubulo-cystic, solid, mixed patterns), grade, mitotic index, association with endometriosis including atypical endometriosis/intraepithelial carcinoma, stage and survival. Nearly 70% of all the patients were diagnosed as stage I. The 2-year and 5-year survival (all stages) was 78% and 68%, respectively. Striking clinicopathologic differences were observed between cystic and adenofibromatous CCCs. Cystic CCC was more frequently diagnosed as stage I compared with adenofibromatous CCC (75% vs. 44%). Conversely, adenofibromatous CCCs were diagnosed more often in advanced stages (stages II-IV) compared with cystic CCCs (56% vs. 18%). Both the cystic and adenofibromatous CCC forms were associated with endometriosis and atypical endometriosis/intraepithelial carcinoma, but the frequency was much higher in the cystic group. Specifically, endometriosis was found in 91% of cystic CCCs and atypical endometriosis/intraepithelial carcinoma in 62% of these cases, whereas endometriosis was found in 44% of adenofibromatous CCCs and atypical endometriosis/intraepithelial carcinoma in 11% of cases. A predominantly papillary pattern was seen in 47% of cystic CCCs, whereas none of the adenofibromatous carcinomas displayed a predominantly papillary pattern. A more favorable outcome was observed for cystic CCCs compared with adenofibromatous CCCs (all stages) which was accounted for by the high proportion of stage I tumors. The 2-year and 5-year survival for the cystic CCCs was 82% and 77% and for the adenofibromatous CCCs (all stages), 62% and 37%, respectively. In summary, subdividing ovarian CCCs into cystic and adenofibromatous CCC reveals differences in a number of clinicopathologic features including their association with endometriosis, histologic patterns, stage distribution, and clinical behavior. Because there were a relatively small number of adenofibromatous CCCs in this series, additional cases must be studied to confirm these findings.
Smoking in Irritable Bowel Syndrome: A Systematic Review

ABSTRACT Objective: The aim of this review was to examine (1) the prevalence of smoking in subjects with irritable bowel syndrome (IBS), (2) whether smoking prevalence significantly differs between subjects with and without IBS, and (3) whether smoking significantly predicts the presence or the development of IBS. Methods: Articles were retrieved by systematically searching the Scopus, Web of Science, and PubMed electronic databases from inception to July 2016, using the keywords “smoking” and “tobacco” combined with “irritable bowel syndrome. ” Reference lists of included articles were also searched. Articles were included if they (1) reported data on smoking prevalence in subjects with IBS and/or on the association (assessed by means of multivariate analyses) between smoking and IBS, (2) identified IBS according to Manning criteria or Rome I–III criteria, (3) were English-language articles, and (4) involved only adult subjects. Results: The electronic searches yielded a total of 1,637 records, and 42 articles met inclusion criteria. Another 13 articles were retrieved through manual search, leading to a total of 55 included articles. Smoking prevalence in subjects with IBS was assessed by 48 articles and ranged from 0% in university students to 47.1% in patients with microscopic colitis. Thirty-three articles compared smoking prevalence between subjects with and without IBS. In 25 articles no significant difference was found. In seven articles smoking was significantly more frequent in subjects with IBS compared to those without IBS, while one study found a significantly higher smoking prevalence in controls. Eighteen multivariate analyses assessing the association between smoking and IBS were presented in 16 articles. Only one study employed a prospective design. In 11 analyses, smoking was not significantly associated with IBS after adjusting for covariates. In seven studies smoking independently predicted the presence of IBS. Conclusions: According to the selected articles, a significant association between smoking and IBS cannot be confirmed. However, different shortcomings may hinder generalizability and comparability of many studies. A dimensional assessment of smoking, a prospective design, the differentiation between IBS subgroups, and the recruitment of patients in clinical settings, especially in primary care, are necessary to clarify the role of smoking in IBS.
Distribution and stability of aflatoxin M1 during production and storage of yoghurt

Yoghurt from cow's milk artificially contaminated with aflatoxin M1 (AFM1) at levels of 0.050 and 0.100 g l-1 was fermented to reach pHs 4.0 and 4.6. Yoghurt fermented to pH 4.6 was also used for preparing strained yoghurt. Yoghurts were stored at 4°C for up to 4 weeks. Analysis of AFM1 in milk, yoghurt, strained yoghurt and yoghurt whey was carried out using immunoaffinity column extraction and liquid chromatography coupled with fluorometric detection. AFM1 levels in yoghurt samples showed a significant decrease (p < 0.01) compared with those initially added to milk. Growth of culture lactic acid bacteria was not affected in the AFM1 contaminated yoghurts, with the exception of Streptococcus thermophilus that showed a significantly (p < 0.01) lower increase in the yoghurt containing the toxin at high concentration. Following fermentation, AFM1 was significantly lower (p < 0.01) in yoghurts with pH 4.0 than in yoghurts with pH 4.6 at both contamination levels. During refrigerated storage, AFM1 was rather more stable in yoghurts with pH 4.6 than with pH 4.0. The percentage loss of the initial amount of AFM1 in milk was estimated at about 13 and 22% by the end of the fermentation, and 16 and 34% by the end of storage for yoghurts with pHs 4.6 and 4.0, respectively. The percentage distribution ratio of AFM1 in strained yoghurt/yoghurt whey of the initial toxin present in the yoghurt was about 90/10 and 87/13 for the lower and the higher contamination levels, respectively.
OxyR, a positive regulator of hydrogen peroxide-inducible genes in Escherichia coli and Salmonella typhimurium, is homologous to a family of bacterial regulatory proteins.

The oxyR gene is required for the induction of a regulon of hydrogen peroxide-inducible genes in Escherichia coli and Salmonella typhimurium. The E. coli oxyR gene has been cloned and sequenced, revealing an open reading frame (305 amino acids) that encodes a 34.4-kDa protein, which is produced in maxicells carrying the oxyR clone. The OxyR protein shows homology to a family of positive regulatory proteins including LysR in E. coli and NodD in Rhizobium. Like them, oxyR appears to be negatively autoregulated: an oxyR::lacZ gene fusion produced 5-fold higher levels of beta-galactosidase activity in oxyR null mutants compared to oxyR+ controls, and extracts from an OxyR-overproducing strain were able to protect regions (-27 to +21) of the oxyR promoter from DNase I digestion. DNA sequence analysis of the oxyR2 mutation, which causes overexpression of oxyR-regulated proteins in the absence of oxidative stress, showed that the oxyR2 phenotype is due to a missense mutation (C.G to T.A transition) that changes alanine to valine at amino acid position 234 of OxyR.
Knockout and humanized mice as suitable tools to identify enzymes metabolizing the human carcinogen aristolochic acid

Abstract 1. Aristolochic acid I (AAI) is the predominant component in plant extract of Aristolochia genus that is involved in development of aristolochic acid nephropathy, Balkan endemic nephropathy and urothelial cancer. The diseases do not develop in all individuals exposed to AAI and patients exhibit different clinical outcomes. Differences in the activities of enzymes catalyzing the metabolism of AAI might be one of the reasons for this individual susceptibility. 2. Understanding which human enzymes are involved in reductive activation of AAI generating AAI-DNA adducts, and/or its detoxication to the O-demethylated metabolite, aristolochic acid Ia (AAIa), is necessary in the assessment of the susceptibility to this compound. 3. This review summarizes the results of the latest studies utilizing genetically engineered mouse models to identify which human and rodent enzymes catalyze the reductive activation of AAI to AAI-DNA adducts and its oxidative detoxication to AAIa in vivo. 4. The use of hepatic cytochrome P450 (Cyp) reductase null (HRN) mice, in which NADPH:Cyp oxidoreductase (Por) is deleted in hepatocytes, Cyp1a1(−/−), Cyp1a2(−/−) single-knockout, Cyp1a1/1a2(−/−) double-knockout and CYP1A-humanized mice revealed that mouse and human CYP1A1 and 1A2, besides mouse NAD(P)H:quinone oxidoreductase, were involved in the activation of AAI but CYP1A1 and 1A2 also oxidatively detoxified AAI.
Recent progress on patchy colloids and their self-assembly

‘Patchy colloids’ is a term that has been recently introduced to indicate specially engineered particles with directional interactions. Based on this concept, a ‘bottom-up’ process for fabricating functional materials and devices has been envisioned, which employs colloidal building blocks and mimics molecular bonding. This article reviews recent progress which has been made in the synthesis and self-assembly of patchy colloids and discusses future directions as well as unresolved challenges.
Nickel sensitization and ear piercing in an unselected Danish population

The study aimed at evaluating nickel sensitization and ear piercing in an unselected population. A questionnaire and ready‐to‐apply patch tests (TRUE‐Test) were mailed to 793 subjects, aged 15 to 69 years. A total of 567 (71.5% out of the 793) were patch tested. The tests were read 2 days after application. Nickel sensitization was diagnosed in 11.1% of the females and in 2.2% of the males. Independent of sex, old age was associated with a lower risk of nickel sensitization (p <0.01). The risk of nickel sensitization was independent of a history of flexural eczema (p>0.5). Ear piercing was more common in the young than in the older age groups, ranging from 30.5% to 0.0% in men, and from 91.5% to 42.9% in women, Sensitization lo nickel was found in 14.8% of those with pierced ears as compared to 1.8% among those without pierced ears. When adjusted for the effects of sex and age, the risk of nickel sensitization among those with pierced ears remained significantly increased and the odds ratio value was 4.5: the 95% confidence interval of the odds ratio value was 1.5 to 13.0. The study confirmed that nickel sensitization in the general population is common, particularly among women. Ear piercing is probably an important risk factor for nickel sensitization.
Mitochondrial Ca2+ homeostasis during Ca2+ influx and Ca2+ release in gastric myocytes from Bufo marinus

The Ca2+‐sensitive fluorescent indicator rhod‐2 was used to monitor mitochondrial Ca2+ concentration ([Ca2+]m) in gastric smooth muscle cells from Bufo marinus. In some studies, fura‐2 was used in combination with rhod‐2, allowing simultaneous measurement of cytoplasmic Ca2+ concentration ([Ca2+]i) and [Ca2+]m, respectively. During a short train of depolarizations, which causes Ca2+ influx from the extracellular medium, there was an increase in both [Ca2+]i and [Ca2+]m. The half‐time (t½) to peak for the increase in [Ca2+]m was considerably longer than the t½ to peak for the increase in [Ca2+]i. [Ca2+]m remained elevated for tens of seconds after [Ca2+]i had returned to its resting value. Stimulation with caffeine, which causes release of Ca2+ from the sarcoplasmic reticulum (SR), also produced increases in both [Ca2+]i and [Ca2+]m. The values of t½ to peak for the increase in [Ca2+] in both cytoplasm and mitochondria were similar; however, [Ca2+]i returned to baseline values much faster than [Ca2+]m. Using a wide‐field digital imaging microscope, changes in [Ca2+]m were monitored within individual mitochondria in situ, during stimulation of Ca2+ influx or Ca2+ release from the SR. Mitochondrial Ca2+ uptake during depolarizing stimulation caused depolarization of the mitochondrial membrane potential. The mitochondrial membrane potential recovered considerably faster than the recovery of [Ca2+]m. This study shows that Ca2+ influx from the extracellular medium and Ca2+ release from the SR are capable of increasing [Ca2+]m in smooth muscle cells. The efflux of Ca2+ from the mitochondria is a slow process and appears to be dependent upon the amount of Ca2+ in the SR.
Combination of doxazosin and sildenafil exerts an additive relaxing effect compared with each compound alone on human cavernosal and prostatic tissue.

INTRODUCTION Phosphodiesterase 5 inhibitors (PDE5) such as sildenafil are first-line treatment for erectile dysfunction (ED). Alpha1 (alpha1)-adrenoceptor antagonists such as doxazosin are indicated for the treatment of patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). ED and LUTS/BPH are conditions that are often associated. Accordingly, alpha1-adrenoceptor antagonists and PDE5 inhibitors will be often prescribed in real life setting together. AIM To evaluate the effects of the combination of sildenafil and doxazosin on human cavernosal and prostatic tissue. METHODS Prostatic and erectile tissues were obtained from nine to 12 patients, respectively. Patients underwent cystoprostatectomy for infiltrating bladder cancer or penile surgery for penile implant, congenital curvature or Peyronie's disease. MAIN OUTCOME MEASURES In organ baths, prostatic and cavernosal strips were submitted to either concentration-response curves (CRC) to phenylephrine (Phe) or norepinephrine (NE), respectively, in presence of vehicle, sildenafil (10(-6) M, 10(-5) M), doxazosin (10(-8) M, 3.10(-8) M, or 10(-7) M), or a combination of both. Continuous electrical field stimulation (EFS; 32 Hz, 5 ms, 5 seconds, 300 mA) was performed on prostatic strips which were incubated with sildenafil 10(-6) M or vehicle before the successive addition of doxazosin (10(-7) M, 10(-6) M) or vehicle. Cavernosal strips were pre-incubated with doxazosin (10(-9) M, 10(-8) M) or vehicle, then CRC to sildenafil were constructed on NE (3.10(-6) M) precontracted cavernosal strips. RESULTS Combination of sildenafil and doxazosin exerted a greater relaxing effect on CRC to Phe or NE compared with each compound alone in both tissues. Sildenafil significantly enhanced the relaxing effect of doxazosin on EFS-induced contractions in prostatic strips. Doxazosin significantly increased the ability of sildenafil to inhibit NE-induced contractions in cavernosal strips. CONCLUSIONS Sildenafil and doxazosin reduced adrenergic tone of prostatic and cavernosal smooth muscle and their combination provided a significant benefit when targeting relaxation of both tissues. These experiments provide support for further clinical evaluation of the sildenafil and doxazosin combination in ED patients with LUTS/BPH.
Transmission ratio distortion at the growth hormone gene (GH1) in bovine preimplantation embryos: An in vitro culture‐induced phenomenon?

The growth hormone gene (GH1) and its polypeptide product (GH) have a crucial role in reproduction, embryogenesis and general development. A polymorphism present in the fifth exon of the bovine GH1 gene (GH1 p.Leu127Val) has been associated with GH release and milk production in cattle. The objective of the present study was to examine the genotype frequencies of the GH1 p.Leu127Val polymorphism in bovine blastocysts produced in vitro and in vivo to determine if allelic variation of the GH1 gene affects embryo development and survival. A heterozygous (p.Leu127/Val127) sire was used for in vitro fertilization of oocytes of unknown maternal genotype (n = 104) and known maternal genotype (n = 115). PCR amplification and genotyping of the GH1 gene from Day 8 blastocysts derived from these fertilized oocytes demonstrated that there was significant over‐representation from the expected Mendelian ratio of GH1 p.Leu127/Leu127 homozygotes from oocytes of known maternal genotype (P = 0.006). Contrary to this, analysis of in vivo‐produced bovine blastocysts of known parental GH1 genotype (n = 69) did not reveal an overrepresentation of GH1 p.Leu127/Leu127 homozygotes. These results suggest that developing in vitro‐produced embryos are exposed to a selection process, probably due to a less favorable culture environment, that acts to increase the number of GH1 p.Leu127/Leu127 homozygotes, thereby giving rise to the observed transmission ratio distortion (TRD) of GH1 genotypes when compared to in vivo produced embryos. Mol. Reprod. Dev. 75: 715–722, 2008. © 2007 Wiley‐Liss, Inc.
Blood pressure changes during daytime sleep and comparison of daytime and nighttime sleep-related blood pressure changes in patients with chronic renal failure.

Blood pressure has a diurnal pattern primarily related to activity and sleep. Chronic renal failure patients may lack the normal nocturnal decline in blood pressure during sleep. In 33 subjects (14 with normal renal function and 19 with renal dysfunction), the relationship between depth of daytime sleep, as determined by electroencephalographic sleep phase, and change in mean arterial blood pressure (MAP) and heart rate measured oscillometrically, was correlated. In 15 chronic renal failure patients, the effect of daytime and nighttime sleep on MAP and heart rate was compared. The percent change in night asleep versus day awake MAP and heart rate was measured (with Space Labs ambulatory blood pressure monitors) and compared with the percent change in daytime sleep-related MAP and heart rate measured during a daytime sleep electroencephalographic study. During daytime sleep, MAP changes are not significantly different in the normal versus renal dysfunction groups. In the 33 study subjects, MAP declines progressively from the upright position to Phase 3/4 sleep (118 +/- 3.6 to 106 +/- 3.6 mm Hg). The largest decline occurs between the upright to recumbent position, before sleep. Heart rate declines moving from the upright to recumbent position, 76 +/- 2.3 to 70 +/- 2.1 beats/min, but does not decline further with sleep. In 15 chronic renal failure patients, heart rate (10.8 +/- 2.8%; P < 0.05), but not MAP, declines during nighttime sleep. Both MAP (7.7 +/- 3.3%) and heart rate (5.4 +/- 1.9%) decline significantly during daytime sleep. The responses of MAP and heart rate to daytime and nighttime sleep were in opposite directions in 3 of 15 subjects. (ABSTRACT TRUNCATED AT 250 WORDS)
CD4 T-Cell Epitopes Associated with Protective Immunity Induced following Vaccination of Mice with an Ehrlichial Variable Outer Membrane Protein

ABSTRACT The ehrlichiae express variable outer membrane proteins (OMPs) that play important roles in both pathogenesis and host defense. Previous studies revealed that OMPs are immunodominant B-cell antigens and that passive transfer of anti-OMP antibodies can protect SCID mice from fatal ehrlichial infection. In this study, we used a model of fatal monocytotropic ehrlichiosis caused by Ehrlichia bacteria from Ixodes ovatus (IOE) to determine whether OMP immunization could generate protective immunity in immunocompetent mice. Immunization of C57BL/6 mice with a purified recombinant OMP expressed by IOE omp19 generated protection from fatal IOE infection and elicited robust humoral and CD4 T-cell responses. To identify CD4 T-cell epitopes within OMPs, we performed enzyme-linked immunospot analyses for gamma interferon (IFN-γ) production using a panel of overlapping 16-mer peptides from IOE OMP-19. Five immunoreactive peptides comprising residues 30 to 45, 77 to 92, 107 to 122, 197 to 212, and 247 to 264 were identified; the strongest response was generated against OMP-19107-122. Most of the peptides are conserved between E. muris and E. chaffeensis OMP-19, and they elicited IFN-γ production in CD4 T cells from E. muris-infected mice, indicating that T-cell epitope cross-reactivity likely contributes to heterologous immunity. Accordingly, CD4 T-cell responses to both OMP-19 and OMP-19107-122 were of greater magnitude following high-dose IOE challenge of mice that had been immunized by prior infection with E. muris. Our studies cumulatively identify B- and T-cell epitopes that are associated with protective homologous and heterologous immunity during ehrlichial infection.