Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulation of Sarcoplasmic Reticulum Ca2+ ATPase 2 (SERCA2) Activity by Phosphodiesterase 3A (PDE3A) in Human Myocardium

Background: PDE3A is part of a SERCA2 signaling complex in cardiac myocytes. Results: PDE3, not PDE4, regulates the activation of SERCA2 by PKA in human myocardium; phosphorylation of PDE3A1 at Ser-292/Ser-293 promotes its integration into the SERCA2 signaling complex. Conclusion: PDE3A1 regulates cAMP-mediated control of SERCA2 through its phosphorylation-dependent interaction with SERCA2. Significance: Targeted disruption of the PDE3A1-SERCA2 interaction may provide a new therapeutic approach for heart failure. Cyclic nucleotide phosphodiesterase 3A (PDE3) regulates cAMP-mediated signaling in the heart, and PDE3 inhibitors augment contractility in patients with heart failure. Studies in mice showed that PDE3A, not PDE3B, is the subfamily responsible for these inotropic effects and that murine PDE3A1 associates with sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2), phospholamban (PLB), and AKAP18 in a multiprotein signalosome in human sarcoplasmic reticulum (SR). Immunohistochemical staining demonstrated that PDE3A co-localizes in Z-bands of human cardiac myocytes with desmin, SERCA2, PLB, and AKAP18. In human SR fractions, cAMP increased PLB phosphorylation and SERCA2 activity; this was potentiated by PDE3 inhibition but not by PDE4 inhibition. During gel filtration chromatography of solubilized SR membranes, PDE3 activity was recovered in distinct high molecular weight (HMW) and low molecular weight (LMW) peaks. HMW peaks contained PDE3A1 and PDE3A2, whereas LMW peaks contained PDE3A1, PDE3A2, and PDE3A3. Western blotting showed that endogenous HMW PDE3A1 was the principal PKA-phosphorylated isoform. Phosphorylation of endogenous PDE3A by rPKAc increased cAMP-hydrolytic activity, correlated with shift of PDE3A from LMW to HMW peaks, and increased co-immunoprecipitation of SERCA2, cav3, PKA regulatory subunit (PKARII), PP2A, and AKAP18 with PDE3A. In experiments with recombinant proteins, phosphorylation of recombinant human PDE3A isoforms by recombinant PKA catalytic subunit increased co-immunoprecipitation with rSERCA2 and rat rAKAP18 (recombinant AKAP18). Deletion of the recombinant human PDE3A1/PDE3A2 N terminus blocked interactions with recombinant SERCA2. Serine-to-alanine substitutions identified Ser-292/Ser-293, a site unique to human PDE3A1, as the principal site regulating its interaction with SERCA2. These results indicate that phosphorylation of human PDE3A1 at a PKA site in its unique N-terminal extension promotes its incorporation into SERCA2/AKAP18 signalosomes, where it regulates a discrete cAMP pool that controls contractility by modulating phosphorylation-dependent protein-protein interactions, PLB phosphorylation, and SERCA2 activity.
Relation of femoral diameter, shear rate, and dilatory response to knee extensor exercise.

INTRODUCTION Younger women typically exhibit marked dilation of the common femoral artery (CFA) during knee extensor exercise; this is in apparent contrast to subject groups with larger (men) and/or older (older women) vessels, which on average display much smaller exercise-induced increases in CFA diameter. To gain additional insight into this variation, the present study closely examined within- and between-group relationships among CFA diameter, shear rate, and the magnitude of exercise-induced CFA dilation. METHODS Healthy women (15 younger and 18 older) and men (15 younger and 13 older) performed graded single-leg knee extensor exercise while CFA diameter and blood velocity were measured using Doppler ultrasound. RESULTS Resting CFA diameter was smaller (P < 0.05) in women (younger: 0.71 ± 0.02 cm; older: 0.72 ± 0.02 cm) compared with men (younger: 0.84 ± 0.01 cm; older: 0.97 ± 0.03 cm). Resting CFA diameter was inversely associated with peak shear rate (combined groups: r = -0.83, P < 0.001) and the magnitude of dilation in women (younger: r = -0.82; older: r = -0.73, P < 0.001) and younger men (r = -0.66, P < 0.01) but not in older men (r = -0.17, P = 0.56). The dilatory response of the CFA to graded increases in shear rate showed a continuum across groups best described by a quadratic function (r2 = 0.89). Using piecewise regression modeling, a threshold diameter of 0.79 cm was identified below which diameter is inversely related to the magnitude of CFA dilation but above which little to no dilation was present. CONCLUSIONS The CFA dilates to knee extensor exercise in women and men, the magnitude of which varies because of differences in shear rate across CFA diameters.
Mitochondrial tRNA 5′-Editing in Dictyostelium discoideum and Polysphondylium pallidum*

Background: Secondary structure modeling predicts 5′-editing of mitochondrial tRNAs in amoebozoans Dictyostelium discoideum and Polysphondylium pallidum. Results: Experimental verification reveals unexpected instances of editing and species-specific variations. Conclusion: Mitochondrial tRNA 5′-editing is a complex process in which 3′–5′ RNA polymerases play a key role. Significance: Further biochemical characterization of mitochondrial tRNA 5′-editing reactions and enzymes is indicated. Mitochondrial tRNA (mt-tRNA) 5′-editing was first described more than 20 years ago; however, the first candidates for 5′-editing enzymes were only recently identified in a eukaryotic microbe (protist), the slime mold Dictyostelium discoideum. In this organism, eight of 18 mt-tRNAs are predicted to be edited based on the presence of genomically encoded mismatched nucleotides in their aminoacyl-acceptor stem sequences. Here, we demonstrate that mt-tRNA 5′-editing occurs at all predicted sites in D. discoideum as evidenced by changes in the sequences of isolated mt-tRNAs compared with the expected sequences encoded by the mitochondrial genome. We also identify two previously unpredicted editing events in which G-U base pairs are edited in the absence of any other genomically encoded mismatches. A comparison of 5′-editing in D. discoideum with 5′-editing in another slime mold, Polysphondylium pallidum, suggests organism-specific idiosyncrasies in the treatment of U-G/G-U pairs. In vitro activities of putative D. discoideum editing enzymes are consistent with the observed editing reactions and suggest an overall lack of tRNA substrate specificity exhibited by the repair component of the editing enzyme. Although the presence of terminal mismatches in mt-tRNA sequences is highly predictive of the occurrence of mt-tRNA 5′-editing, the variability in treatment of U-G/G-U base pairs observed here indicates that direct experimental evidence of 5′-editing must be obtained to understand the complete spectrum of mt-tRNA editing events in any species.
A systematic review of patient reported outcomes and patient experience in enhanced recovery after orthopaedic surgery.

INTRODUCTION Orthopaedic enhanced recovery after surgery (ERAS) providers are encouraged to estimate the actual benefit of ERAS according to the patient's opinion by using patient generated data alongside traditional measures such as length of stay. The aim of this paper was to systemically review the literature on the use of patient generated information in orthopaedic ERAS across the whole perioperative pathway. METHODS Publications were identified using Embase(™), MEDLINE(®), AMED, CINAHL(®) (Cumulative Index to Nursing and Allied Health Literature), the Cochrane Library and the British Nursing Index. Search terms related to experiences, acceptance, satisfaction or perception of ERAS and quality of life (QoL). FINDINGS Of the 596 abstracts found, 8 papers were identified that met the inclusion criteria. A total of 2,208 patients undergoing elective hip and knee arthroplasty were included. Patient satisfaction was reported in 6 papers. Scores were high in all patients and not adversely affected by length of stay. QoL was reported in 2 papers and showed that QoL scores continued to increase up to 12 months following ERAS. Qualitative methods were used in one study, which highlighted problems with support following discharge. There is a paucity of data reporting on patient experience in orthopaedic ERAS. However, ERAS does not compromise patient satisfaction or QoL after elective hip or knee surgery. The measurement of patient experience should be standardised with further research.
Discrimination between different types of white matter edema with diffusion‐weighted MR imaging

Brain edema can be classified into three categories: vasogenic, cytotoxic, and interstitial. The mechanism of edema is thought to be different in each type. The authors studied the movement of water molecules in each type of white matter edema in a rat model by using diffusion‐weighted magnetic resonance imaging. Conventional T2‐weighted imaging did not allow distinction between the three types of white matter edema; the three types of edema were, however, distinguished by using diffusion‐weighted imaging. The apparent diffusion coefficient (ADC) of water was different in each type of edema. Water molecules in cytotoxic edema induced by triethyl‐tin intoxication showed a smaller and less anisotropic ADC than in normal white matter. In contrast, water in vasogenic edema induced by cold injury had a larger and more anisotropic ADC than in normal white matter. Water in interstitial edema due to kaolin‐induced hydrocephalus had an anisotropic and very large ADC.
Estimating corporate profit shifting with firm-level panel data: time trends and industrial heterogeneity

Base erosion and profit shifting (BEPS) undermines tax revenues collection and raise public discontent in times when the tax burden has increased significantly for households in most developed economies. In such context the need to have dependable estimations of profit shifting is warranted both in order to quantify the extent of BEPS and to devise policy measures in order to tackle it. Several studies have assessed the sensitivity of profit shifting activities by multinational companies. Earlier studies have tended to rely on cross-sections of firms, while more recent researches have exploited panel data and, on average, found lower semi-elasticities. The latter has sometimes been interpreted as evidence of a decline in profit shifting during the more recent period. In this paper we argue that such interpretation might be far-fetched and we show that these results can largely be attributed to differences in methods and data used. Our evidence suggests instead that the variability in profit shifting rests primarily on sector heterogeneity and that this may have important methodological and policy implications. We propose an alternative estimation strategy based on multilevel regression analysis exploiting cross-sectoral heterogeneity to yield more robust estimates of profit shifting elasticities. Our multilevel estimates point to an overall semi-elasticity of about -0.47, meaning that for a rise in CIT rate of 10% we expect pre-tax profits to decrease by 4.7%. Our semi-elasticity is lower than the "consensus" estimate of -0.8 and in line with more recent studies that exploit panel data. We find that the semi-elasticities vary significantly across industries with a standard deviation more than ten times the estimated average semi-elasticity. When comparing transfer pricing activities with financial shifting we find the former to be much more sensitive to the tax rate than the latter. We also find that the presence of intangible assets affects transfer pricing elasticities but only when the firm belongs to specific industries.
Post‐Transplant Infections Now Exceed Acute Rejection as Cause for Hospitalization: A Report of the NAPRTCS 1

Newer immunosuppressive agents have dramatically reduced the rates of acute graft rejection (AR) over the last decade but may have exacerbated the problem of post‐transplant infections (PTI). We analyzed data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to determine the risks of hospitalization from PTI vs. AR in the years 1987–2000. For patients transplanted in 1987, the AR‐associated hospitalization rate exceeded the equivalent hospitalization rate for PTI at both early (1–6 months) and later time points (6–24 months). In contrast, for patients transplanted in the year 2000, the PTI‐associated hospitalization rate was twice that for AR‐associated hospitalization during each time period. During the first two years post‐transplant, rates of AR hospitalization trended significantly downwards (p < 0.001) while rates of PTI‐associated hospitalization stayed constant. In the 6–24‐month time period post‐transplant, the risk of bacterial and viral infection‐related hospitalization rose significantly from 1987 to 2000 (p < 0.001 for trend by transplant year). We conclude that the causes of hospitalization at all times up to 24 months post‐transplant, including the critical early 6 months, have shifted away from AR to PTI.
Intracellular potassium ion activity in resting and stimulated mouse pancreas and submandibular gland

Intracellular potassium ion activities (aiK+) and membrane potentials were measured with double-barrelled, potassium-specific microelectrodes in superfused mouse pancreas and submandibular gland. Stimulation with the cholinergic agonist bethanechol caused a marked decrease in aiK+ in the submandibular gland, whereas no change in aiK+ could be detected in the pancreas. This indicates that bethanechol increases the permeability of the cell membranes to potassium ions in the submandibular gland but not in the pancreas. Pancreatic acinar cells hyperpolarized promptly when the extracellular potassium ion activity was restored after a prolonged period of potassium deprivation. In comparison, the recovery of aiK+ was a slow process. This finding gives support to the view that the hyperpolarization is due to electrogenic sodium pumping.
Localized 13C NMR spectroscopy of myo‐inositol in the human brain in vivo

Natural abundance 13C NMR spectra obtained from 144‐cm3volumes in the human brain contained well‐resolved resonances of myo‐inositol after 60 min of data accumulation. A mean concentration of 7.2 ± 0.5 pmol/g (±SE, n = 7) was calculated from the comparison with phantoms. 13C NMR spectroscopy thus provides a complementaryrole in the quantitation of metabolites also observed in the crowded 1H spectrum.
Price of adaptation--allostatic load and its health consequences. MacArthur studies of successful aging.

BACKGROUND Exponential growth in the population of older adults presents clinicians with special concerns about factors affecting risks for declines in cognitive and physical functioning. OBJECTIVES To examine the hypothesis that risks for such declines and for disease outcomes, such as cardiovascular disease, are related to differences in allostatic load, the cumulative physiologic toll exacted on the body over time by efforts to adapt to life experiences. To present an operational definition of allostatic load, along with preliminary evidence of its predictive validity in relation to salient outcomes of aging. METHODS Data from a longitudinal, community-based study of successful aging were used to develop a measure of allostatic load based on 10 parameters reflecting levels of physiologic activity across a range of important regulatory systems. Allostatic load is the sum of the number of parameters for which the subject was rated in the highest-risk quartile. RESULTS Higher allostatic load scores were associated with poorer cognitive and physical functioning and predicted larger decrements in cognitive and physical functioning as well as being associated with an increased risk for the incidence of cardiovascular disease, independent of sociodemographic and health status risk factors. CONCLUSIONS Findings are consistent with the conceptualization of allostatic load as an index of wear and tear on the body, with elevations in allostatic load predicting an increased risk for a decline in cognitive and physical functioning as well as cardiovascular disease in a cohort of older men and women. From a clinical perspective, the concept of allostatic load may provide the basis for a more comprehensive assessment of major risks in the aging process.
The Politics of European Public Health Data

This chapter examines the effect of public health data on European policy-making. Political stakeholders of all kinds and at all levels of government are frequently observed making non-trivial use of public health data, often in the form of indicators such as mortality rates or expenditure levels. Virtually all forms of strategic reasoning and communicative action are infused with such indicators, most of which have become increasingly available to decision-makers through national and supranational administrative units, academic research centers and third parties like think tanks or international organizations. Nothing about public health data might therefore be deemed entirely new, but their widespread diffusion within and across borders suggests that their political effects may increase.
Microstructure analysis of price discovery, information-based trading and intervention in foreign exchange markets

Motivated by the disconnection between dealer-level (DL) and market-level (ML) models, and the inadequacy of theoretical macro models in explaining the behaviour of the exchange rate, this thesis first studies the microstructure of the foreign exchange market and links the behaviour of dealers to exchange rate determination. We develop a model incorporating both information effect and inventory effect in an environment that is closer to reality. Secondly, the order flow model explains around 13% of exchange rate movement per transaction for CNY/USD. In addition, we adopt the probability of information-based trading (PIN) model and the autoregressive conditional duration (ACD) model to directly study the information content of trading duration in the Chinese foreign exchange market. The estimated results provide some evidence that both the expected component and the unexpected component of trading duration are relevant to the arrival rate of informed traders. Signed expected and unexpected trading durations of order flow are proven to contain information in addition to order flow. The final effect of trading duration is a composite result between uninformed and informed traders. Therefore, the impact of trading duration differs according to different market situations. Thirdly, using the Logit model and Ordered Logit model in the estimation, we find that the Chinese government prefers a gradual achievement of its target exchange rate, and ‘leans-against-the-wind’ with a 150-day moving average and target appreciation rate. The driving force of intervention is asymmetric and dynamic. In addition, the Chinese government is found to show more tolerance toward USD appreciation (CNY depreciation) than to USD depreciation (CNY appreciation), except during periods when it actively accelerates the appreciation of CNY to counter a high rate of inflation. Our model is proved to perform better than OLS estimation and to improve prediction ability.
Nonlinear trend stationarity in global and hemispheric temperatures

ABSTRACT This study investigates the issue of whether our Earth’s surface temperature exhibits a stochastic trend. Using state-of-the-art econometrics, we analyse the latest available temperature anomaly data. Our results indicate that both global and hemispheric temperatures may appear to have a stochastic trend when in fact they are stationary around a nonlinear deterministic trend and structural breaks are responsible. Furthermore, the nonlinearity found in the temperature trend is more complex than what has been reported in previous studies.
Disparate lympho‐erythroid donor to recipient chimaerism in a β°‐thalassaemia bone marrow transplant recipient with red cell indices indicative of apparent full engraftment

A 4‐year‐old girl with transfusion‐dependent β°‐thalassaemia received an HLA‐identical bone marrow transplant (BMT) from her β°‐thalassaemia trait sister. Prior to BMT, chromosomal analysis revealed the recipient to have 46,XX,9qh+, a polymorphic variant of the heterochromatin region of chromosome 9, which her donor did not have. Within 1 month post‐BMT, 89% of nucleated bone marrow cells were of donor origin. One year later, donor engraftment had decreased to 44% and 34% in nucleated bone marrow cells and blood lymphocytes, respectively. By 2 years, donor lymphocyte engraftment fell to 5%, raising concern of possible graft rejection. To examine erythroid chimaerism, globin synthesis by individual erythroid progenitor cell derived colonies (BFU‐E) was analysed. On days 1000 and 1130 post‐BMT, 79% and 77% of colonies, respectively, synthesized β‐globin and therefore were of donor origin.
Genetic Epidemiological Approaches to the Search for Osteoporosis Genes

Important progress has been made in the identification of specific environmental factors and estimation of hereditary components in bone density, quantitative ultrasound (QUS), and bone turnover indices. By contrast, the search for specific genes that regulate bone mass has progressed rather slowly, and the results are more difficult to interpret and reproduce. This article reviews the genetics of osteoporosis and problems plaguing genetic research. It is argued that the search for genes involved in the expression of osteoporotic phenotypes should be based on linkage studies in relatively homogeneous populations. Strategies for increasing the power of studies, such as making use of information from extended pedigrees and multivariate analysis, are discussed. With the advent of a comprehensive human genetic linkage map, a complete identification of genes for osteoporosis appears feasible. Understanding the genetic mechanisms and their interactions with environmental factors should allow more focused and cost‐effective osteoporosis prevention and treatment strategies.
Th17 profile in COPD exacerbations

COPD is characterized by an ongoing inflammatory process of the airways that leads to obstruction or limitation of airflow. It is mainly associated with exposure to cigarette smoke. In addition, it is considered, at present, a serious public health problem, ranking fourth in mortality worldwide. Many cells participate in the pathophysiology of COPD, the most important are neutrophils, macrophages and CD4+ and CD8+ T cells. Neutrophil migration to the inflammation area could be mediated largely by cytokines related to CD4+ Th17 lymphocytes, because it has been shown that IL-17A, IL-17F and IL-22 act as inducers for CXCL8, CXCL1, CXCL5, G-CSF, and GM-CSF secretion by epithelial cells of the airways. The aims of these molecules are differentiation, proliferation and recruitment of neutrophils. Furthermore, it is believed that CD4+ lymphocytes Th17 may be involved in protection against pathogens for which Th1 and Th2 are not prepared to fight. In COPD exacerbations, there is an increased cellularity in the lung region and respiratory tract. Therefore, the increase in the number of neutrophils and macrophages in the airways and the increase in proinflammatory cytokines are directly related to the severity of exacerbations and that is the importance of the functions of Th17 profile in this entity.