Miracle-dz/UniFAR-FTUs huggingface dataset:
Application of CYP3A4 in vitro data to predict clinical drug-drug interactions; predictions of compounds as objects of interaction.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Numerous retrospective analyses have shown the utility of in vitro systems for predicting potential drug-drug interactions (DDIs). Prediction of DDIs from in vitro data is commonly obtained using estimates of enzyme K(i), inhibitor and substrate concentrations and absorption rate for substrate and inhibitor. WHAT THIS STUDY ADDS Using a generic approach for all test compounds, the findings from the current study showed the use of recombinant P450s provide a more robust in vitro measure of P450 contribution (fraction metabolized, f(m)) than that achieved when using chemical inhibitors in combination with human liver microsomes, for the prediction of potential CYP3A4 drug-drug interactions prior to clinical investigation. The current study supported the use of SIMCYP(R), a modelling and simulation software in utilizing the in vitro measures in the prediction of potential drug-drug interactions. AIMS The aim of this study was to explore and optimize the in vitro and in silico approaches used for predicting clinical DDIs. A data set containing clinical information on the interaction of 20 Pfizer compounds with ketoconazole was used to assess the success of the techniques. METHODS The study calculated the fraction and the rate of metabolism of 20 Pfizer compounds via each cytochrome P450. Two approaches were used to determine fraction metabolized (f(m)); 1) by measuring substrate loss in human liver microsomes (HLM) in the presence and absence of specific chemical inhibitors and 2) by measuring substrate loss in individual cDNA expressed P450s (also referred to as recombinant P450s (rhCYP)) The fractions metabolized via each CYP were used to predict the drug-drug interaction due to CYP3A4 inhibition by ketoconazole using the modelling and simulation software SIMCYP. RESULTS When in vitro data were generated using Gentest supersomes, 85% of predictions were within two-fold of the observed clinical interaction. Using PanVera baculosomes, 70% of predictions were predicted within two-fold. In contrast using chemical inhibitors the accuracy was lower, predicting only 37% of compounds within two-fold of the clinical value. Poorly predicted compounds were found to either be metabolically stable and/or have high microsomal protein binding. The use of equilibrium dialysis to generate accurate protein binding measurements was especially important for highly bound drugs. CONCLUSIONS The current study demonstrated that the use of rhCYPs with SIMCYP provides a robust in vitro system for predicting the likelihood and magnitude of changes in clinical exposure of compounds as a consequence of CYP3A4 inhibition by a concomitantly administered drug.
Do smart tourism destinations really work? The case of Benidorm

ABSTRACT Smart Destinations (SDs) have gained momentum in tourism research, but despite the growing body of literature devoted to the topic, some critical dimensions continue to be under-researched. Real fulfilment of two of the main objectives of SDs, namely enhancing tourists’ experiences and improving destinations management, remains largely unknown. By taking as a relevant case the destination of Benidorm, its smart destination strategy and solutions, this paper investigates whether and how these smart destination efforts are actually transforming destination management, marketing processes and tourists’ experiences. Through a sequence of qualitative methods including (i) documentary and other secondary data analysis, (ii) in-depth interviews with DMO representatives and key informants and (iii) in-depth interviews with tourists visiting the destination, rich data was obtained, systematically analysed and triangulated. The findings pose critical lessons for destinations in their transition towards smartness, especially for policy-makers, and shed light on the effects of smart solutions on tourist experiences.
Effects of Influenza A Virus NS1 Protein on Protein Expression: the NS1 Protein Enhances Translation and Is Not Required for Shutoff of Host Protein Synthesis

ABSTRACT The influenza A virus NS1 protein, a virus-encoded alpha/beta interferon (IFN-α/β) antagonist, appears to be a key regulator of protein expression in infected cells. We now show that NS1 protein expression results in enhancement of reporter gene activity from transfected plasmids. This effect appears to be mediated at the translational level, and it is reminiscent of the activity of the adenoviral virus-associated I (VAI) RNA, a known inhibitor of the antiviral, IFN-induced, PKR protein. To study the effects of the NS1 protein on viral and cellular protein synthesis during influenza A virus infection, we used recombinant influenza viruses lacking the NS1 gene (delNS1) or expressing truncated NS1 proteins. Our results demonstrate that the NS1 protein is required for efficient viral protein synthesis in COS-7 cells. This activity maps to the amino-terminal domain of the NS1 protein, since cells infected with wild-type virus or with a mutant virus expressing a truncated NS1 protein—lacking approximately half of its carboxy-terminal end—showed similar kinetics of viral and cellular protein expression. Interestingly, no major differences in host cell protein synthesis shutoff or in viral protein expression were found among NS1 mutant viruses in Vero cells. Thus, another viral component(s) different from the NS1 protein is responsible for the inhibition of host protein synthesis during viral infection. In contrast to the earlier proposal suggesting that the NS1 protein regulates the levels of spliced M2 mRNA, no effects on M2 protein accumulation were seen in Vero cells infected with delNS1 virus.
Using Hoechst 33342 to Target Radioactivity to the Cell Nucleus

Abstract Yasui, L. S. , Chen, K. , Wang, K. , Jones, T. P., Caldwell, J., Guse, D. and Kassis, A. I. Using Hoechst 33342 to Target Radioactivity to the Cell Nucleus. Radiat. Res. 167, 167–175 (2007). We have explored the use of Hoechst 33342 (H33342) to carry radioactivity to the cell nucleus. H33342 enters cells and targets DNA at adenine-thymine-rich regions of the minor groove. Considerable membrane blebbing and ruffling occur in CHO cells within minutes after its addition to the culture medium in micromolar quantities. Blue vesicles are apparent in the cell cytoplasm, and by 30 min the nuclei are stained dark blue. Upon its binding to DNA, a visible emission shift of the dye can be observed with fluorescence microscopy. We have radioiodinated (125I) H33342 and specifically irradiated nuclear DNA by incubating CHO cells with 125I-H33342 at 37°C and accumulating 125I decays at −90°C. At various times, the cells are thawed and assayed for survival (clonogenicity) and DSB (γ-H2AX) formation. 125I-H33342 decay leads to a monoexponential decrease in cell survival with a D0 of 122 125I decays per cell and a linear increase in DNA DSB induction (equivalent to 15 γ-H2AX foci/cell). Cell death is not modified by the radioprotective effects of H33342 because we use considerably lower concentrations than those that provide a slight protection against γ radiation. We conclude that cell killing by 125I-H33342 and the induction of γ-H2AX foci are highly correlated.
Neighborhoods of Choice and Connection: The Evolution of American Neighborhood Policy and What It Means for the United Kingdom

C asual visitors to America’s great cities are often struck by the vast areas of deprivation that abut vibrant downtowns, major freeways, urban rail yards, and once-grand commercial corridors. In a suburban nation that treasures the “new,” these places stand out for their visible poverty and often-dilapidated, sometimes-vacant housing and commercial structures. Bearing the mark of a succession of government programs, these communities seem strangely out of place in this prosperous country—a grim reminder of the racial, ethnic, and class divisions that persist beneath celebrations of the American dream. Since the 1960s, such run-down neighborhoods have held a fascination for scholars and journalists, conservative theorists and liberal thinkers. These precincts have been the laboratories for a plethora of foundation experiments, government demonstrations, and federal policies and programs. And yet, the impact of these efforts—amounting to tens of billions of dollars over several decades—remains decidedly mixed. To be sure, some neighborhoods can point to real improvements. But many initiatives—despite the best of intentions—have failed to alleviate, and in some cases have exacerbated, the deteriorating economic and social conditions in inner cities. This paper prepared for delivery as the Joseph Rowntree Foundation’s Centenary Event in London surveys the contours of American neighborhood policy since the 1960s and proposes a new goal for such work in the U.S. and U.K.: the creation of “neighborhoods of choice and connection. ” The paper opens with an overview of the nature of American neighborhood distress and how leaders have responded to it in recent decades. This section contends that three distinct sets of neighborhood policies have emerged over time and that there are strengths and limitations to each. Drawing on this analysis of the American experience, the paper then provides a series of observations on how community leaders and policymakers on both sides of the Atlantic can embrace a new neighborhood paradigm that seeks to attract residents of all strata while linking them also to goodquality education, training, and other routes to economic opportunity. Neighborhoods of Choice and Connection: The Evolution of American Neighborhood Policy and What It Means for the United Kingdom
Prognostic indices in childhood heart failure.

OBJECTIVES To evaluate the short term prognosis of childhood heart failure and highlight the factors that affect outcome among cases of heart failure admitted into the paediatric wards, University College Hospital, Ibadan. BACKGROUND Childhood heart failure remains a major cause of morbidity and mortality in the developing world. The advent of open heart surgery, use of better myocardial preservative techniques, and the introduction of newer, more effective drugs in the treatment of heart failure have greatly improved the outcome of children with heart failure in the developed world. The outlook of such children in the developing world however remains poor. METHODS One hundred consecutive cases of heart failure admitted into the Paediatric wards of the University College Hospital, Ibadan with a diagnosis of heart failure over a 10-month period were studied prospectively. Diagnosis of heart failure was based on the presence of at least three of the four cardinal signs of heart failure: tachypnoea, tachycardia, tender hepatomegaly and cardiomegaly. All cases were followed up daily till a definite outcome was determined. RESULTS The predominant underlying causes of heart failure were acute respiratory infections (36%), severe anaemia (28%), and congenital heart disease (25%). There was a case-fatality rate of 24% among the study population. Poor prognostic indices identified were age below one year or above 5 years, presence of underlying acute respiratory infections, rheumatic heart disease and renal disorders. CONCLUSION Heart failure in Nigerian children though mostly due to preventable causes, are associated with an unacceptably high mortality.
Clinical and pathological features in hydrocarbon‐induced Parkinsonism

A neuropathological examination was performed on a patient with parkinsonism induced by prolonged exposure to a mixture of aliphatic hydrocarbons, mainly n‐hexane and halogenated compounds. The patient developed a rapid‐course disease that progressed even after with‐drawal from the toxic exposure. Pathological examination and immunohistochemical analysis of the brain revealed severe and widespread dopaminergic neuronal loss, associated with severe gliosis, in the substantia nigra, and almost complete loss of tyrosine hydroxylase immunostaining in the striatum. No Lewy bodies were detected. Neuronal loss was also observed in the periaqueductal gray matter, locus ceruleus, and pedunculopontine nucleus. These changes, combined with the moderate anemia due to marrow suppression, and the mild axonal neuropathy observed in vivo, are suggestive of a hydrocarbon toxic insult.
Understanding and Reducing Persistent Poverty in Africa

his paper introduces a special issue exploring persistent poverty in sub-Saharan Africa. As a set, these papers break new ground in exploring the dynamics of structural poverty, integrating qualitative and quantitative methods of analysis and adopting an asset-based approach to the study of changes in well-being, especially in response to a wide range of different (climatic, health, political, and other) shocks. In this introductory essay, we frame these studies, building directly on evolving conceptualisations of poverty in Africa.
Estimating Macroeconomic Models of Financial Crises: An Endogenous Regime-Switching Approach

We estimate a workhorse DSGE model with an occasionally binding borrowing constraint. First, we propose a new specification of the occasionally binding constraint, where the transition between the unconstrained and constrained states is a stochastic function of the leverage level and the constraint multiplier. This specification maps into an endogenous regime-switching model. Second, we develop a general perturbation method for the solution of such a model. Third, we estimate the model with Bayesian methods to fit Mexico's business cycle and financial crisis history since 1981. The estimated model fits the data well, identifying three crisis episodes of varying duration and intensity: the Debt Crisis in the early-1980s, the Peso Crisis in the mid-1990s, and the Global Financial Crisis in the late-2000s. The crisis episodes generated by the estimated model display sluggish and long-lasting build-up and stagnation phases driven by plausible combinations of shocks. Different sets of shocks explain different variables over the business cycle and the three historical episodes of sudden stops identified.
Stock Market Liberalizations and Export Dynamics

We find that granting foreign investors access to domestic stock markets facilitate efficiency-enhancing product specialization in the recipient countries. After countries liberalize their stock markets and allow foreign investors to acquire equity stakes in domestic firms, products that do not correspond to the liberalizing countries' comparative advantage disappear disproportionately faster from their export portfolios. At the same time, the overall long-term export performance of the liberalizing countries improves. Domestic stock market development does not play the same disciplining role in forcing termination of inefficient exports, suggesting a unique role for foreign investors in improving resource allocation in the real economy.
Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis

Accumulating evidence indicates that abnormal conformation of mutant superoxide dismutase 1 (SOD1) is an essential feature underlying the pathogenesis of mutant SOD1‐linked familial amyotrophic lateral sclerosis (ALS). Here we investigated the role of ubiquitin‐proteasome pathway in the mutant SOD1‐related cell death and the effect of oxidative stress on the misfolding of mutant SOD1. Transient overexpression of ubiquitin with human SOD1 (wild‐type, ala4val, gly85arg, gly93ala) in Neuro2A cells decreased the amount of mutant SOD1, but not of wild‐type, while only mutants were co‐immunoprecipitated with poly‐ubiquitin. Proteasome inhibition by lactacystin augmented accumulation of mutant SOD1 in the non‐ionic detergent‐insoluble fraction. The spinal cord lysates from mutant SOD1 transgenic mice showed multiple carbonylated proteins, including mutant SOD1 with SDS‐resistant dimer formation. Furthermore, the treatment of hSOD1‐expressing cells with hydrogen peroxide promoted the oligomerization, and detergent‐insolubility of mutant SOD1 alone, and the oxidized mutant SOD1 proteins were more heavily poly‐ubiquitinated. In Neuro2A cells stably expressing human SOD1 protein, the proteasome function measured by chymotrypsin‐like activity, was decreased over time without a quantitative alteration of the 20S proteasomal component. Finally, primary motor neurons from the mouse embryonic spinal cord were more vulnerable to lactacystin than non‐motor neurons. These results indicate that the sustained expression of mutant SOD1 leads to proteasomal inhibition and motor neuronal death, which in part explains the pathogenesis of mutant SOD1‐linked ALS.
Assessing the effect of foreign direct investment and foreign trade on the competitiveness of Arab economies : an econometric approach using panel data

In spite of the Arab region having a comparative advantage in natural resources and other factor endowments such as labour and capital, the region’s competitiveness ranking is weak when judged globally. In particular, inflows of foreign direct investment and foreign trade volumes are not commensurate with what would be expected for this group of countries, given their factor endowments and comparative advantage. The purpose of this thesis is to analyse the low competitiveness rankings obtained by Arab countries, and to analyse the viability of improving this competitiveness by enhancing foreign trade and foreign direct investment in the region. This is a topic that, to the best of our knowledge, has not previously been researched at all for Arab countries in the empirical economics literature. First, we set out the conceptual underpinnings of competitiveness and the ways in which a country's competitiveness is measured in practice. We then apply Generalized Method of Moments (GMM) in a dynamic panel data model with fixed effects, in order to estimate the effect of foreign direct investment and foreign trade on the competitiveness of Arab countries. The dataset covers 17 Arab countries, spanning the period 1998-2009. We adopt panel data methodology, by applying. The results of the empirical model reveal that FDI inflows and foreign trade both have a positive impact on the competitiveness of Arab economies. In addition, control variables reflecting macroeconomic management in Arab countries such as domestic credit to the private sector, corruption, inflation, labour productivity and nominal exchange rate are found to be significantly and positively related to competitiveness. On the other hand, interaction terms for FDI and trade with economic freedom were found to be insignificant. We then offer policy recommendations, based on these findings.
Phase I study of eptifibatide in patients with sickle cell anaemia

The αIIbβ3 antagonist eptifibatide is an effective treatment for patients with acute coronary syndromes (ACS). Platelet reactivity and CD40 ligand (CD40L) may play a role in the pathophysiology of sickle cell anaemia (SCA) similar to that in ACS, suggesting that inhibition of platelet aggregation and CD40L release by eptifibatide may benefit patients with SCA. Following eptifibatide infusion, safety and pharmacodynamic data were obtained from four SCA patients in their non‐crisis, steady states. Eptifibatide was well tolerated, with no adverse changes in the haematological, biochemical or coagulation parameters studied. Eptifibatide did not increase plasma levels of platelet factor 4 or beta‐thromboglobulin, P‐selectin exposure or platelet:leucocyte aggregate formation. Moreover, decreases in platelet aggregation and soluble CD40L (sCD40L) levels achieved in SCA patients were comparable to those observed in the treatment of ACS. Finally, indicators of inflammation, macrophage inflammatory protein‐1α, tumour necrosis factor‐α and myoglobin were reduced following eptifibatide infusion, while vasodilation correlatives, matrix metalloproteinases (MMP‐2 and MMP‐9) and leptin were increased. Based on these phase I results, eptifibatide may benefit SCA patients by inhibiting platelet aggregation, decreasing sCD40L levels and favourably altering plasma levels of inflammatory mediators.
Sensory Changes and Loss of Intraepidermal Nerve Fibers in Painful Unilateral Nerve Injury

ObjectivesDysaesthesias is a common symptom in patients with neuropathic pain after peripheral nerve injury (PNI). In contrast to neuropathies with comparable symptoms there is little knowledge of the underlying mechanisms in PNI patients. MethodsQuantitative sensory testing according to the German Research Network on Neuropathic Pain protocol, and changes in intraepidermal nerve fiber density were assessed in 15 patients with dysaesthesias after PNI of the lower limb. According to their small-fiber function patients were assigned into 2 subgroups. ResultsThe sensory profiles of PNI patients were characterized predominantly by minus symptoms (significantly increased thresholds for perception of cold, warm, touch and vibration, and significantly increased thresholds for heat and mechanical pain) on the affected compared with the unaffected side. The only plus symptom reported was a significantly reduced pressure pain threshold. The sensory profile of patients with a severe loss of small-fiber function (n=7) showed a thermal and tactile hypoaesthesia and hypoalgesia; this was in contrast to patients with a moderate loss of small-fiber function, who showed a mild thermal and tactile hypoaesthesia associated with an increased mechanical pain sensitivity. Mean intraepidermal nerve fiber density was significantly decreased in the affected compared with unaffected skin [3.50 (4.00) vs. 11.10 (7.60) fibers/mm] and correlated with warm and mechanical detection thresholds (both r=−0.60). DiscussionIn conclusion, even though patients presented with comparable clinical symptoms, their sensory profiles differed, supporting the concept of different underlying mechanisms leading to chronic pain in PNI patients. Skin biopsies support the validity of quantitative sensory testing.
The Determinants and Effects of Clients Following Audit Partners Who Switch Audit Firms

Abstract We examine the determinants of clients’ decision to follow departing partners to new audit firms and the effect of this decision on the likelihood of financial restatements. Using Taiwanese audit partner turnover data from 1984 to 2010, we find that clients are more likely to follow departing partners when the partners have more clients, longer tenure, and when both lead and concurring partners leave simultaneously. By contrast, clients are more likely to stay with their incumbent audit firms when the firms are one of the Big Four or when only the concurring partners leave. The extended partner tenure due to clients following departing partners, however, does not enhance audit quality. In fact, clients that stay at the incumbent firm experience a significant decrease in the probability of financial restatements in the first year after the audit partners leave, but clients that follow do not.