Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential Incorporation and Removal of Antiviral Deoxynucleotides by Human DNA Polymerase γ*

Mitochondrial toxicity can result from antiviral nucleotide analog therapy used to control human immunodeficiency virus type 1 infection. We evaluated the ability of such analogs to inhibit DNA synthesis by the human mitochondrial DNA polymerase (pol γ) by comparing the insertion and exonucleolytic removal of six antiviral nucleotide analogs. Apparent steady-stateK m and kcat values for insertion of 2′,3′-dideoxy-TTP (ddTTP), 3′-azido-TTP (AZT-TP), 2′,3′-dideoxy-CTP (ddCTP), 2′,3′-didehydro-TTP (D4T-TP), (-)-2′,3′-dideoxy-3′-thiacytidine (3TC-TP), and carbocyclic 2′,3′-didehydro-ddGTP (CBV-TP) indicated incorporation of all six analogs, albeit with varying efficiencies. Dideoxynucleotides and D4T-TP were utilized by pol γ in vitro as efficiently as natural deoxynucleotides, whereas AZT-TP, 3TC-TP, and CBV-TP were only moderate inhibitors of DNA chain elongation. Inefficient excision of dideoxynucleotides, D4T, AZT, and CBV from DNA predicts persistencein vivo following successful incorporation. In contrast, removal of 3′-terminal 3TC residues was 50% as efficient as natural 3′ termini. Finally, we observed inhibition of exonuclease activity by concentrations of AZT-monophosphate known to occur in cells. Thus, although their greatest inhibitory effects are through incorporation and chain termination, persistence of these analogs in DNA and inhibition of exonucleolytic proofreading may also contribute to mitochondrial toxicity.
Acquisition of response thresholds for timed performance is regulated by a calcium‐responsive transcription factor, CaRF

Interval timing within the seconds‐to‐minutes range involves the interaction of the prefrontal cortex and basal ganglia via dopaminergic–glutamatergic pathways. Because the secreted protein brain‐derived neurotrophic factor (BDNF) is able to modulate dopamine release as well as glutamatergic activity, we hypothesized that BDNF may be important for these timing mechanisms. Recently, the calcium‐responsive transcription factor (CaRF) was identified as an important modulator of BDNF expression in the cerebral cortex. In this study, a strain of Carf knockout mice was evaluated for their ability to acquire the ‘Start’ and ‘Stop’ response thresholds under sequential and simultaneous training conditions, using multiple (15‐second and 45‐second) or single (30‐second) target durations in the peak‐interval procedure. Both Carf+/− and Carf−/− mice were impaired in their ability to acquire timed response thresholds relative to Carf+/+ mice. Additionally, control mice given microinjections of BDNF antisense oligodeoxynucleotide to inhibit protein expression in the prefrontal cortex showed timing impairments during acquisition similar to Carf mice. Together, these results suggest that the inhibitory processes required to update response thresholds and exert temporal control of behavior during acquisition may be dependent on CaRF regulation of genes including Bdnf in cortico‐striatal circuits.
Total Parenteral Nutrition in Pancreatic Disease

Total parenteral nutrition (TPN) was given to 121 patients admitted with severe pancreatitis (73), chronic pancreatitis (23), or pancreatic malignancy (25) over 104 months. No adverse effects on the pancreas were detected from the TPN, including the provision of intravenous (IV) fat. Nutritional status was maintained or improved in all groups, including patients undergoing surgical procedures and those experiencing marked stress. No significant impact on the clinical course of pancreatitis was observed, although the death rate in acute pancreatitis (15.2%) and complicated pancreatitis (18.5%) compares favorably with other published series where early surgical intervention was undertaken. There was an increased risk of catheter-related sepsis in patients with complicated pancreatitis (14.8%) and with chronic pancreatitis (17.4%). No increase septic risk was seen in patients with acute pancreatitis or pancreatic malignancy. Eighty-two per cent of patients with acute pancreatitis required an average of 87 units of insulin per day while 78% of patients with chronic pancreatitis required an average of 54 units per day. In summary, TPN proved to be safe, effective, and well-tolerated in those patients with disorders of the pancreas.
Analytical rubrics in higher education: A repository of empirical data

The use of rubrics for grading and feedback in higher education has increased inresponse to requirements for consistency and transparency across a diverse range ofassessment tasks. There is a growing evidence base demonstrating the reliability ofrubrics across different markers and instances. The number of studies describing theimpact of rubrics on student learning has also grown; however, these studies arepredominantly qualitative and/or use a quasi-experimental design. Confounding factorsin these studies include the validity and quality of the rubric, markers’ expertise andstudents’ previous experience of using rubrics and learning preferences. This paperdescribes a data set comprising student marks from large cohorts of postgraduatestudents, pre and post the introduction of rubrics on three different modules, and theassociated rubrics. In making these data available under the terms of the CreativeCommons Attribution License, it is hoped to establish a repository of rubrics validatedfor speciﬁc assessment tasks and their associated data sets, to develop robust methods fortheir evaluation and explore methods of rubric deployment for effective learningthrough assessment.
Temperature variation in the 24 hours before the initial symptoms of stroke.

UNLABELLED A few studies have performed to evaluate the temperature variation influences over on the stroke rates in Brazil. METHOD 176 medical records of inpatients were analyzed after having had a stroke between 2004 and 2006 at Hospital Israelita Albert Einstein. The temperature preceding the occurrence of the symptoms was recorded, as well as the temperature 6, 12 and 24 hours before the symptoms in 6 different weather substations, closest to their houses in São Paulo. RESULTS Strokes occurred more frequently after a variation of 3 C between 6 and 24 hours before the symptoms. There were most hospitalizations between 23-24 C. CONCLUSION Incidence of stroke on these patients was increased after a variation of 3 masculine Celsius within 24 hours before the ictus. The temperature variations could be an important factor in the occurrence of strokes in this population.
International Tax Disputes: Between Supranational Administration and Adjudication

The proposals resulting from the G20/Organisation for Economic Cooperation and Development (OECD) project on Base Erosion and Profit Shifting (BEPS) include a drive for mandatory binding arbitration of international tax disputes, strongly supported by business. This issue should be considered in the context of the reasons for and nature of international tax disputes. The bulk of such conflicts concern â€˜economicâ€™ double taxation, resulting from divergent interpretations by different tax authorities of the standards for attributing profits to affiliates within a corporate group, so that the firm as a whole may be taxed on more than 100 per cent of its worldwide profit. Such divergences result from transfer pricing rules that treat the affiliates within a TNC group as if they were an independent entity dealing â€˜at armâ€™s lengthâ€™ with each other, and requiring subjective judgements by each tax authority on the profits attributable to each. Hence, it is not surprising that the number of such conflicts has grown steadily, especially in the past decade, as countries have applied the rules more vigorously. Arbitration has been advocated not because it can provide objective adjudication, but as a fall-back in order to pressurise tax authorities to resolve cases by negotiation rather than submitting to a third party decision. In fact, although binding arbitration has been available among European Union (EU) members as well as some other states since 1990, only a handful of the continually growing number of conflict cases have actually been referred to arbitration. The newer approach of â€˜last best offerâ€™ (LBO) arbitration, widely regarded as more successful, aims to pressurise tax authorities to give up positions that are likely to be considered unorthodox. The Mutual Agreement Procedure (MAP), including arbitration, is essentially a supranational administrative procedure for coordination of the application of international tax rules. Its improvement should form part of a wider process of reform of both the institutions and the substantive rules of international taxation.
Expression of the 17-1A antigen in gastric and gastro-oesophageal junction adenocarcinomas: a potential immunotherapeutic target?

BACKGROUND: A murine monoclonal antibody against the 17-1A epithelial antigen has been shown to be a useful adjuvant therapy in colorectal cancer. Its clinical use could be extended to patients with upper gastrointestinal adenocarcinoma. AIM: To determine the distribution of the antigen in gastric and oesophageal adenocarcinoma. METHODS: The activity of two monoclonal antibodies active against 17-1A epithelial antigen was studied in gastric and gastro-oesophageal junction adenocarcinomas: fresh frozen tissue from both the carcinoma and adjacent mucosa was stained using immunocytochemistry with a murine monoclonal antibody (17-1A edrecolomab, Glaxo Wellcome); paraffin embedded tissue was stained using the humanised monoclonal antibody 3622W94 (Glaxo Wellcome). RESULTS: 29 of 33 cancers (88%) stained with the murine antibody and 39 of 40 (98%) with the humanised antibody. The degree of staining was greater in well differentiated and moderately differentiated tumours. There was no staining of the normal background gastric or oesophageal mucosa, but areas of intestinal metaplasia stained intensely. The humanised monoclonal 3622W94 antibody produced more intense staining than the murine antibody. CONCLUSIONS: The high incidence of expression of the 17-1A antigen in patients with gastric and gastro-oesophageal junction adenocarcinomas suggests a potential role for these antibodies as an adjuvant treatment for these common cancers.
Quinoline resistance mechanisms in Plasmodium falciparum: the debate goes on

Despite considerable therapeutic success with the antimalarial 4-aminoquinolines such as chloroquine, there is serious doubt about the future of this drug class due mainly to the development and spread of parasite resistance throughout endemic areas. In this article we review the possible biochemical and molecular basis of resistance. Based on our current understanding we have considered the possibility of developing strategies which may allow the aminoquinolines to once again be used effectively against P. falciparum. Our conclusions are that drug resistance is the result of a reduced rate of drug uptake which in turn reduces the amount of drug available to bind the target. The basis for this reduced accumulation could be an altered pH gradient making the food vacuole more alkaline or the parasite cytosol more acidic, an efflux pump removing drug directly from the membrane or any other process which will reduce the rate of drug uptake. Central to the effectiveness of this resistance mechanism is the transient availability of a high affinity, low capacity drug binding site (possibly haem) within the parasite. Resistance reversers such as verapamil influence the apparent Ka for this drug binding phenomenon via an increased drug uptake rate. We demonstrate that by chemical modification of the aminoquinolines, producing predictable alterations in their physicochemical properties, that it is possible to minimise the verapamil sensitive component of resistance and reduce significantly cross-resistance patterns without loss in absolute activity. Based on these views we suggest that the aminoquinoline antimalarials still have a role to play in the cheap, safe and effective chemotherapy of falciparum malaria.
UK elected representatives and their weblogs: first impressions

Purpose – To examine the weblogs written by members of UK legislatures and to determine whether such weblogs address commonly cited criticisms of MPs' web sites and serve to bridge the gap between representative and constituent.Design/methodology/approach – Examination of the literature on MPs' web sites to draw up a list of common criticisms. Construction of evaluation criteria to analyse the blogs in terms of content, currency, design, interactivity and evidence of personality both as a snapshot and over a longer period.Findings – That weblogs are, on the whole, kept up to date and show promising levels of activity. Blogs enable constituents to see with what their MPs have been involved (on both the local and the Parliamentary stages) and to see what areas of policy particularly interest their MP. Personality of the MPs is apparent on most of the blogs, which are less party‐oriented than many MPs' web sites. Although the gap between representatives and constituents may have been bridged to an extent, bl.
The Impact of Internal Governance Mechanisms on the Share Price Volatility of Listed Companies in Paris Stock Exchange

This paper investigates the impact of internal governance structure on firm-level stock return volatility in Paris Stock Exchange based on our study of a sample of 65 firms for the daily period from January 2010 to December 2012.The research has sixth hypotheses. To test each hypothesis; a model was defined based on dependent variables employed to measure the share price volatility. Our findings reveal different results by using different models of multivariate regression. The empirical results show no statistically significant relationship to any components of ownership structure. However, the results also show that the components for the board structure reduce volatility. Indeed, we document a statistically significant negative relationship between the board independence, the CEO Duality, the board size and the share price volatility. Hence, the board structure is not expected to cause severe volatility in the stock prices, which in turn, is consistent with the results of this study.
Digital technologies and environmental change: examining the influence of social practices and public policies

Digital technologies and services affect the planet. Every line of code, every photo uploaded to ‘the cloud’, and every smartphone, computer, or ‘IoT’ device, has an environmental footprint. That footprint often takes the form of carbon dioxide emissions, ecosystem degradation, and resource depletion, each of which occur to varying degrees throughout the production, use, and end-of-life processing of digital technologies. In the past two decades, multidisciplinary researchers and practitioners have examined and responded to many aspects of these processes; the responses have taken diverse forms, including energy efficiency and design standards, restrictions on the use of hazardous materials, and the international adoption of rules and regulations about electronics waste (e-waste). Despite these responses, the global environmental footprint of digital technologies and services has continued to rise due to their growing ubiquity, dwindling lifespans, and ‘always on’ support infrastructure. In this thesis, I respond directly to calls for increased analysis and discussion of the social practices and public policies that influence the environmental footprint of digital technologies (e.g. [83, 139, 232]). To narrow the scope of this broad line of enquiry, I focus on the social practices of retrocomputing repairers and human-computer interaction (HCI) academics— two communities whose practices influence the footprint of digital technologies—as well as environmental public policies that influence HCI practitioners. By drawing on secondary data and semi-structured qualitative interviews with 7 retrocomputing repairers and 22 HCI academics, my thesis offers three sets of contributions to complementary and ongoing conversations within the HCI community. The first two sets of contributions focus on the social practices of distinct but indirectly connected communities: retrocomputing repairers and HCI academics. While many HCI academics work to conceive of new digital products and services, the retro repairers actively work to maintain their ageing digital products in the face of increasingly scarce resources. Each group influences the environmental footprint in unique ways, which have been hitherto unexplored. I discuss some of these influences, and use them to highlight questions about existing and future HCI research. The third set of contributions focuses on environmental public policies and HCI. By fusing two existing approaches to understanding public policies and their relevance to HCI, I highlight opportunities for HCI researchers to engage with and influence environmental public policy. This allows me to suggest ways that environmental public policy could influence and be influenced by HCI research.
CD4/CD8 Ratio Predicts Peripheral Fat in HIV-Infected Population

New Haven, CT kPhiladelphia VA Medical Center, Philadelphia, PA ¶Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA #Washington DC VA Medical Center, Washington, DC **George Washington University Medical Center, Washington, DC ††Hamad Healthcare Quality Institute and Hamad Medical Corporation, Doha, Qatar ‡‡VA Pittsburgh Healthcare System, Pittsburgh, PA §§James J. Peters VA Medical Center, Bronx, NY kkIcahn School of Medicine at Mt. Sinai, New York, NY ¶¶Michael E. DeBakey VA Medical Center, Houston, TX ##Baylor College of Medicine, Houston, TX ***Atlanta VA Medical Center, Atlanta, GA †††Emory University School of Medicine, Atlanta, GA ‡‡‡Saint Louis University School of Medicine, Saint Louis, MO
Suicide: an existentialist reconceptualization.

The phenomenon of suicide is one of the primary concerns for mental health professions. The health-care literature is dominated by discussions that focus variously on local and national suicide prevention policies, on the assessment of those individuals judged to be at risk of committing suicide as well as the appropriateness and efficacy of interventions for those who express suicidal ideation and display suicidal behaviours. What appear less frequently in the literature, however, are critical analyses of the concept of suicide and, in particular, critical reflections on the manner in which the concept of suicide has been, and continues to be, understood or 'framed'. In an attempt to respond to this apparent omission, this paper will suggest that the work of Albert Camus, and his philosophical work The Myth of Sisyphus in particular, can be understood as providing a significant reconceptualization and reframing of suicide. In doing so, it will be suggested that Camus's work not only challenges how the concept of suicide has traditionally been situated within the context of mental illness, but can also be understood as challenging the efficacy of the interventions that have been associated with an understanding of suicide within that context.
Elevated Serum Neopterin Predicts Future Cardiac Adverse Events in Patients with Angina Pectoris

Introduction: Neopterin, a pterydine derivative secreted by activated macrophages, has been shown to be associated with vulnerable coronary stenoses in patients with unstable angina. Neopterin has also been associated with coronary artery disease progression. Objective: We sought to assess the prognostic significance of serum neopterin concentrations in patients with angina pectoris. Material and Methods: We carried out a 1-year follow up study in 384 consecutive patients with angina pectoris (297 stable and 87 unstable). The primary study end-point was the composite of nonfatal myocardial infarction, class IIIb unstable angina and cardiac death. Serum neopterin was measured using a commercially available immunoassay (ELISA Kit, IBL, Hamburg , Germany ). Angiographic extent and severity of coronary artery disease were assessed and scored according to a validated method. Results: Seventy four patients (19%) developed at least one major adverse coronary event. Serum neopterin levels were higher in patients with events compared to those without events (6.9 [4.8 to 8.3] vs 5.7 [4.1 to 7.6]; P=0.02). Only neopterin (P= 0.015), number of diseased vessels with =50% reduction in lumen diameter (P=0.005) and a history of MI (P<0.0001) remained independent predictors of the combined end-point. There was a significant gradual increase in the number of adverse events during the one-year follow-up with increasing of neopterin tertiles (p<0.001). After adjustment using binary logistic regression, patients in the highest tertile of neopterin distribution (>7 nmol/L) had an almost 3-fold higher risk of adverse cardiovascular events (OR 2.9 [1.4 to 6.2] CI 95%; P=0.006) compared to those in the lowest tertile (<4.8 nmol/L). Conclusions: Neopterin is an independent predictor of adverse cardiac events in patients with angina pectoris. Our results suggest that this marker of macrophage activation and atherosclerotic disease activity may be useful for risk stratification in patients with coronary artery disease.
Employee Engagement – the Emergence of a New Construct?

Employee engagement is a useful recent concept in HRM: it is a composite construct that describes inter alia employees' commitment, job satisfaction and involvement. Increasingly, employee engagement has also come to be recognised as making a significant difference to performance at all levels within the company. But there still exists some vagueness about the meaning of the term: how exactly may employee engagement be defined? This article presents a genealogy of the new construct.
Pharmacotherapy for comorbidities in chronic heart failure: a focus on hematinic deficiencies, diabetes mellitus and hyperkalemia

ABSTRACT Introduction: Chronic heart failure (HF) is frequently accompanied by one or more comorbidities. The presence of comorbidities in chronic HF is strongly correlated to HF severity and impaired outcome. Areas covered: This review will address several comorbidities with high prevalence and/or high impact in patients with chronic HF, including diabetes, anemia, hematinic deficiencies, and hyperkalemia. The background and subsequent pharmacotherapeutic options of these comorbidities will be discussed. For this review, a MEDLINE search was performed. Expert opinion: Heart failure is increasingly considered a multimorbid syndrome, including metabolic derangements and chronic inflammation. Persistent metabolic derangements and low-grade inflammation might lead to progression of HF and the development of comorbidities. Although several comorbidity-specific drugs became available in the past decade, most of these therapies are studied in relatively small cohorts using surrogate end-points. Therefore, larger studies are needed to address whether treating these comorbidities will improve patient outcome in chronic HF.