Miracle-dz/UniFAR-FTUs huggingface dataset:
(Z)- and (E)-2-(Hydroxymethylcyclopropylidene)-Methylpurines and Pyrimidines as Antiviral Agents

Several Z- and E-methylenecyclopropane nucleoside analogues were synthesized and evaluated for antiviral activity. Reaction of the Z- and E-2-amino-6-chloropurine methylenecyclopropanes with ammonia or cyclopropylamine gave 2,6-diamino or 2-amino-6-cyclopropylamino analogues. Alkylation elimination of N4-acetylcytosine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave a mixture of the Z-and E-methylenecyclopropane derivatives of cytosine. Reduction furnished a mixture of syncytol and the E isomer. Benzoylation led to the respective N4-benzoyl derivatives which were separated by chromatography. Debenzoylation afforded pure syncytol and the E isomer. Alkylation of 2,4-bis-O-trimethylsilylthymine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave the corresponding Z- and E-1-bromo-cyclopropylmethylderivatives of thymine. Base-catalysed elimination of HBr gave Z- and E-methylenecyclopropane carboxylic esters. Reduction furnished, after chromatographic separation, synthymol and the E isomer. The Z/E isomeric assignment of the obtained products followed from 1H NMR spectroscopy. The methylenecyclopropane analogues were tested for antiviral activity in vitro against human and murine cytomegalovirus (HCMV, MCMV), Epstein–Barr virus (EBV), varicella zoster virus (VZV), hepatitis B virus (HBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1). The Z-2-amino-6-cyclopropylaminopurine analogue was the most effective agent against HCMV (EC50 or EC90 0.4–2 μM) followed by syncytol and the Z-2,6-diaminopurine analogues (EC50 or EC90 3.4–29 and 11–24 μM, respectively). The latter compound was also a strong inhibitor of MCMV (EC50 0.6 μM). Syncytol was the most potent against EBV (EC50 <0.41 and 2.5 μM) followed by the Z-2,6-diaminopurine (EC50 1.5 and 6.9 μM) and the Z-2-amino-6-cyclopropylaminopurine derivative (EC50 11.8 μM). Syncytol was also most effective against VZV (EC50 3.6 μM). Activity against HSV-1, HSV-2 and HHV-6 was generally lower; synthymol had an EC50 of 2 μM against HSV-1 (ELISA) and 1.3 μM against EBV in Daudi cells but was inactive in other assays. The 2-amino-6-cyclopropylamino analogue displayed EC50 values between 215 and >74 μM in HSV-1 and HSV-2 assays. 2-Amino-6-cyclopropylaminopurine and 2,6-diaminopurine derivatives were effective against HBV (EC50 2 and 10 μM, respectively), whereas none of the analogues inhibited HIV-1 at a higher virus load. Syncytol and the E isomer were equipotent against EBV in Daudi cells but the E isomer was much less effective in DNA hybridization assays. The E-2,6-diaminopurine analogue and E isomer of synthymol were devoid of antiviral activity.
Large scale real‐time PCR analysis of mRNA abundance in rainbow trout eggs in relationship with egg quality and post‐ovulatory ageing

The mRNA levels of 39 target genes were monitored in unfertilized eggs of 14 rainbow trout sampled the day of ovulation and again 5, 14, and 21 days later. For all 56 collected egg batches, an egg sample was fertilized to estimate egg quality by monitoring embryonic development. Remaining eggs were used for RNA extraction and subsequent real‐time PCR analysis. A significant drop of egg quality was observed when eggs were held in the body cavity for 14 or 21 days post‐ovulation (dpo). During the same period, eight transcripts (nucleoplasmin or Npm2, ferritin H, tubulin β, JNK1, cyclin A1, cyclin A2, cathepsin Z, and IGF2) exhibited a differential abundance at one or several collection time(s). Interestingly, we observed higher levels of cyclins A1 and A2 mRNAs in eggs taken 5 days post‐ovulation than in eggs taken, from the same females, at the time of ovulation. In addition, seven transcripts exhibited a differential abundance between low quality and high quality eggs. Low quality eggs were characterized by lower levels of Npm2, tubulin β, and IGF1 transcripts. In contrast, keratins 8 and 18, cathepsin Z, and prostaglandin synthase 2 were more abundant in low quality eggs than in high quality eggs. In this study, we have demonstrated differences in mRNA levels in the rainbow trout egg that are reflective of developmental competence differences induced by post‐ovulatory ageing. The putative role of these transcripts in post‐ovulatory ageing‐induced egg quality defects is discussed with special attention for corresponding cellular functions. Mol. Reprod. Dev. © 2005 Wiley‐Liss, Inc.
Idiopathic pulmonary fibrosis: outcome in relation to smoking status.

RATIONALE The pathogenic importance of smoking status in idiopathic pulmonary fibrosis (IPF) is uncertain. In theory, increased oxidative stress in current and former smokers might promote disease progression. However, better survival has been reported for current smokers with IPF, although this might reflect less severe disease at presentation (a "healthy smoker effect"). OBJECTIVES To determine whether smoking status is associated with survival differences in IPF. METHODS A total of 249 patients with IPF were studied (current smokers, n = 20; former smokers, n = 166; never-smokers, n = 63). Survival was evaluated against smoking status, using proportional hazards analysis, adjusting for sex, age, disease severity (extent of the disease on high-resolution computed tomography, composite physiologic index [CPI], percentage predicted diffusing capacity for carbon monoxide in separate models), and the degree of honeycombing. MEASUREMENTS AND MAIN RESULTS Current smokers had milder disease than did former smokers, with lower CPI scores (P < 0.0001), less extensive disease on high-resolution computed tomography (P < 0.005), and higher unadjusted survival (hazard ratio = 0.44; 95% confidence interval = 0.24, 0.80; P = 0.007). However, survival did not differ between current and former smokers (P = 0.39) after adjustment for CPI levels. By contrast, the increase in survival seen in nonsmokers than in former smokers (hazard ratio = 0.51; 95% confidence interval = 0.41, 0.83; P = 0.008) was amplified (P < 0.0005) by adjustment for CPI levels. CONCLUSIONS In IPF, survival and severity-adjusted survival are higher in nonsmokers than in former smokers or the combined group of former and current smokers. By contrast, a better outcome in current smokers, compared with former smokers, reflects less severe disease at presentation and may represent a healthy smoker effect.
Effects of Perturbing Nucleoid Structure on Nucleoid Occlusion-Mediated Toporegulation of FtsZ Ring Assembly

ABSTRACT In Escherichia coli, assembly of the FtsZ ring (Z ring) at the cell division site is negatively regulated by the nucleoid in a phenomenon called nucleoid occlusion (NO). Previous studies have indicated that chromosome packing plays a role in NO, as mukB mutants grown in rich medium often exhibit FtsZ rings on top of diffuse, unsegregated nucleoids. To address the potential role of overall nucleoid structure on NO, we investigated the effects of disrupting chromosome structure on Z-ring positioning. We found that NO was mostly normal in cells with inactivated DNA gyrase or in mukB-null mutants lacking topA, although some suppression of NO was evident in the latter case. Previous reports suggesting that transcription, translation, and membrane insertion of proteins (“transertion”) influence nucleoid structure prompted us to investigate whether disruption of these activities had effects on NO. Blocking transcription caused nucleoids to become diffuse, and FtsZ relocalized to multiple bands on top of these nucleoids, biased towards midcell. This suggested that these diffuse nucleoids were defective in NO. Blocking translation with chloramphenicol caused characteristic nucleoid compaction, but FtsZ rarely assembled on top of these centrally positioned nucleoids. This suggested that NO remained active upon translation inhibition. Blocking protein secretion by thermoinduction of a secA(Ts) strain caused a chromosome segregation defect similar to that in parC mutants, and NO was active. Although indirect effects are certainly possible with these experiments, the above data suggest that optimum NO activity may require specific organization and structure of the nucleoid.
Ultrastructural localization of cell membrane GM1 ganglioside by cholera toxin.

An immunoelectron microscopic method is described for sensitive high-resolution visualization of tissuebound cholera toxin. The principle is to incubate cells or tissue sections with toxin and then to localize the bound toxin with toxin-specific peroxidase (donor:hydrogen-peroxide oxidoreductase; EC 1.11.1.7)-conjugated antibody and enzyme substrate. Thin sections are examined for electron-opaque precipitates in a transmission electron microscope. Because of the specific binding of the toxin to membrane ganglioside G(M1), the method can be used for ultrastructural localization of this ganglioside. Semiquantitative data are obtained by titration of the limiting concentration of cholera toxin producing specific precipitates. The specificity of the method was controlled in various ways, including analyses of the correlation between the immunoelectron microscopy results and determinations of ganglioside G(M1) in tissues with different ganglioside concentrations, tissues hydrolyzed with Vibrio cholerae sialidase, tissues in which exogenous G(M1) has been incorporated, and lipid-extracted tissues. The immunoelectron microscopic method demonstrates that membrane G(M1) ganglioside is positioned on the external side exclusively. Cell-bound toxin remains in its original location on the plasma membrane surface of cells below 18 degrees , but appears to be redistributed both laterally and vertically in the membrane of cells incubated at 37 degrees for 30 min or longer. The results of this method indicate that in the central nervous system G(M1) is concentrated in the pre- and postsynaptic membranes of the synaptic terminals; a further increase in reactivity of these structures after hydrolysis of the nervous tissue with V. cholerae sialidase suggests that higher gangliosides of the same series are particularly increased in the pre- and postsynaptic junctions.
Early detection of viral resistance by determination of hepatitis B virus polymerase mutations in patients treated by lamivudine for chronic hepatitis B

We have analyzed the molecular dynamics of emergence of drug‐resistant strains in patients receiving lamivudine therapy for chronic hepatitis B. Twenty consecutive patients with lamivudine resistance were studied (13 hepatitis B e antigen [HBeAg]–positive patients and 7 HBe antibody [anti‐HBe]–positive patients). Determination of viral genotype, precore mutants, and polymerase gene mutants (L528M, M552V, M552I) was performed using the research version of Lipa‐HBV. Quantitative analysis of HBV DNA was performed using both branched DNA (bDNA) and polymerase chain reaction (PCR) assays. Polymerase mutants (genotypic resistance) were found in 16 of 20 patients. Genotypic resistance was detected earlier than the phenotypic resistance (P = .004). Quantitative PCR allowed detection of viral DNA throughout the entire study period in 16 of 20 patients. Analysis of pretreatment variables showed that high alanine transaminase (ALT) levels (>3 × the upper limit of normal [ULN]) was associated with a more rapid selection of drug‐resistant mutants (P = .027) and a high hepatitis B virus (HBV) DNA level (>1,497 Meq/mL, bDNA) with a more rapid occurrence of phenotypic resistance (P = .04). At the time of viral breakthrough, the mean serum HBV‐DNA values were not different from the pretreatment values (P = .37). ALT levels were higher in anti‐HBe–positive patients compared with pretreatment values and to HBeAg‐positive patients (P = .01). In 8 patients, antiviral therapy was modified after viral breakthrough, with the introduction of famciclovir and/or interferon alfa. Viral DNA became undetectable by bDNA in 3 patients who received interferon. Our results suggest that genotypic assays for polymerase mutant detection and quantitative determination of viremia with highly sensitive assay are warranted for an optimal monitoring of antiviral therapy of chronic hepatitis B.
How to measure sickness absence? Literature review and suggestion of five basic measures

Objective — To examine different sick-leave measures used in sickness absence research, and to suggest a systematic way of assessing sickness absence. Methods — A review and analysis of five major studies on sick-leave performed 1983—1988 with an epidemiological approach. Results — Terminology and measures used varied in the different studies reviewed. The choice of a certain measure was seldom discussed in relation to the aim of the study. Based on the review five measures are suggested: frequency, length, incidence rate, cumulative incidence and duration. The definition of incidence rate is new and is a measure useful in studies of recurrent events within epidemiology. Conclusions — We have reviewed sick-leave measures previously used in the literature and suggested five basic measures for assessing sick-leave.
Stable angina – who needs revascularisation?

In the UK, about 5% of men and 3% of women have, or have had, angina.1 Also, estimates suggest that, each year, around 340,000 people present with the symptom for the first time.1 Characterised by pain or discomfort in the chest, angina is usually caused by atherosclerotic coronary artery disease and so carries an increased risk of cardiovascular complications such as myocardial infarction and death from coronary heart disease (CHD). In stable angina, the symptoms are induced by exertion, reflecting the limitation of blood supply through the narrowed arteries and the resulting myocardial ischaemia. The condition is not only potentially distressing, but may also limit daily function and quality of life. To address these problems and the elevated cardiovascular risk, standard management includes lifestyle measures (e.g. physical activity without excessive exertion, stopping smoking, weight control); tackling other cardiovascular risk factors (e.g. raised blood pressure, diabetes mellitus); and medication to control angina (e.g. nitrates, beta-blockers, calcium antagonists) and to reduce overall cardiovascular risk (e.g. aspirin, statin therapy). 2,3 Where such non-invasive measures alone are inadequate, revascularisation (restoration of adequate blood supply to the heart muscle) by using coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) may also be needed. Here we discuss methods for, and difficulties in, assessing patients who present with suspected stable angina to identify those who could benefit from revascularisation.
Evidence-based lifestyle interventions in the workplace--an overview.

BACKGROUND Lifestyle-related health issues affect the economic position of organizations and contribute to reduced productivity, increased absenteeism and health care costs. AIMS To summarize the effectiveness of different workplace health interventions for promoting healthy lifestyle, preventing diseases and reducing health care costs. METHODS We searched MEDLINE via Pubmed, EMBASE, Cochrane Library, NelH, HighWire Press and Google Scholar in March 2012. Systematic reviews and meta-analyses of workplace interventions aimed at promoting physical activity, healthy weight and good nutrition were included. Three authors assessed the quality of the reviews and extracted data on methods, interventions, outcomes, results and effect sizes. RESULTS We identified 15 publications covering a total of 379 original studies. Three systematic reviews found beneficial effects of workplace nutrition interventions on employees' dietary behaviour. Three reviews found multi-component physical activity interventions to be effective in increasing employees' physical activity and fitness. The other activity promotion interventions were less effective regarding physical activity and weight-related outcomes. In terms of weight management, our findings favour multi-component interventions that focus on both physical activity and nutrition over single dietary programmes. CONCLUSIONS Workplace health promotion interventions may improve physical activity, dietary behaviour and healthy weight. There is no evidence of increased efficacy associated with specific intervention types. Workplace health promotion should focus on either physical activity or weight or nutrition behaviour to maximize effectiveness. Best evidence is available for multi-component interventions.
Different antitumor immunity roles of cytokine activated T lymphocytes from naive murine splenocytes and from dendritic cells-based vaccine primed splenocytes: implications for adoptive immunotherapy.

AIM The aim of the study is to explore the antitumor capacity of effector cells generated from murine splenocytes with sequential addition of a cocktail of cytokines and the possible contribution of dendritic cells to the antitumor capacity of these effector cells. METHODS AND RESULTS Interferon-gamma, interleukin (IL)-1 beta, anti-CD3 mAb and IL-2 were used to activate murine splenocytes either from naive mice (termed cytokine activated T cells, CAT) or from DC based vaccine primed mice (termed specific effector T cells, SET). The antitumor roles of SET and CAT were analyzed in murine L615 T lymphocytic leukemia. Both CAT and SET were CD4(+)-predominant phenotypically and didn't show any significant cytotoxicity against a variety of syngeneic and allogeneic target cell lines using 51Cr release assay. When injected in vivo in combination with CY, CAT can cure a large proportion of leukemia mice. The cured mice couldn't establish specific antitumor immunity. However, in contrast to the roles of CAT, SET show far superior antitumor efficacy on a per cell basis compared with CAT. Moreover, the SET cured mice developed tumor specific long term memory immunity which was sufficient to reject a subsequent otherwise lethal tumor cells rechallenge and was transferable to naive immunocompetent mice. CONCLUSION Our data demonstrate that there remain fundamentally different antitumor functions of CAT and SET which might be useful in the immunotherapy strategy choices.
Peri-operative medical management of cerebral vasospasm

Abstract Introduction: The physiological mechanism of cerebral vasospasm after aneurysmal subarachnoid hemorrhage remains elusive and its treatment can be challenging. Traditionally, 'triple-H' therapy and the calcium channel blocker, nimodipine, are used to treat cerebral vasospasm. However, as the etiology of vasospasm is unraveled, investigative pharmaceutical agents that stop the development and attenuate the severity of cerebral vasospasm, are being investigated in clinical trials. Methods: In this manuscript, we review the clinical presentation and characteristics of cerebral vasospasm after aneurysmal subarachnoid hemorrhage and the utility of hyperdynamic therapy and pharmacotherapies. Results: Triple-H therapy improves cerebral perfusion and improves neurological outcome during clinically evident cerebral vasospasm. Nimodipine is the accepted standard medication used to reduce the incidence of cerebral vasospasm, but more importantly, has a neuroprotective effect during hypoxia. Other medications such as magnesium sulfate, HMG-CoA reductase inhibitors and enoxaparin, are also being trialed with some promising results. Conclusion: Endovascular administration of intra-arterial anti-spasmodic agents and balloon angioplasty are becoming more commonly utilized at institutions where endovascular therapy is available. However, triple-H therapy and nimodipine remain the accepted first-line of treatment for cerebral vasospasm after aneurysmal subarachnoid hemorrhage.
MR imaging during endovascular procedures: An evaluation of the potential for catheter heating

MRI in catheterized patients is considered unsafe due to the potential for focal heating. This concern arises from the continuous metallic braid that is incorporated into catheters to provide their desired physical properties. The potential for catheter heating during MR scanning was assessed in an in vitro model simulating a patient undergoing a neurovascular procedure in which MR scans of the brain will be performed. Heating adjacent to endovascular devices was assessed with fluoroptic temperature probes in a polyacrylamide gel. The effect of variable immersion lengths, lateral and longitudinal offsets, position along the endovascular device, physical MR system, and specific absorption rate (SAR) level were studied to determine their effect on catheter heating. A rapid temperature rise was evident next to endovascular devices during MR scanning and varied moderately with immersed length, position within the bore, measurement point on the device, and MR system used. Peak heating rates were less than 1°C/min with maximal SAR exposure and anatomically realistic geometries. Heating scaled linearly with SAR and SAR values below 0.2 W/kg produced negligible heating near catheters. For the evaluated application, substantial SAR restrictions, coupled with limited imaging durations, are proposed as sufficient to permit MRI without concern for thermal injury. Magn Reson Med 61:45–53, 2009. © 2008 Wiley‐Liss, Inc.
[Social Constitution and the form of the Capitalist State], Sosyal Yapı ve Kapitalist Devlet Sorunu

1970’lerin sonundaki devletin kokenine iliskin tartismalarinin yavaslamasindan sonra (1), 1980’lerin basinda neredeyse butun kapitalist ulkelerde devlete olan ilgi, guce vurgu yapan muhafazakârlikla yeniden meydana cikti. Kapitalist devlet uzerine yapilan son calisma (post-)Fordizm uzerindeki tartismalardan etkilenmistir (bkz: Hirsch & Roth, 1986) (2). (Post-)fordist devlet tartismasi, devlet ve ekonomi arasindaki iliskilerdeki degisimi daha iyi bir sekilde anlayabilmek icin devletin daha somut bir sekilde kavramsallastirmasini amaclamaktadir. Burada temel sorun devletin kokeni tartismasini reddetmek degil, bu tartismayi kapitalist gelisme teorisi icerisinde siniflandirmaktir. Bu sekilde, yapi ve catisma arasindaki iliski olarak yillardir Marksist tartismanin konusu olan bu tema, cagdas gelismeler baglaminda daha somut bir sekilde tartisilmaktadir. (Post-)fordizm uzerindeki tartismanin onemli bir zayif noktasinin, yapi ve catismayi eklemlememek oldugunu baska bir yerde tartistim (bkz: Bonefeld, 1987a). Zaten bu zayiflik Hirsch’in devletin kokeni tartismasina yaptigi katkilarda da gorulmustu (bkz: Holloway, 1988).