Miracle-dz/UniFAR-FTUs huggingface dataset:
Aspirin Attenuates Platelet Activation and Immune Activation in HIV-1-Infected Subjects on Antiretroviral Therapy: A Pilot Study

Background:Mechanisms for increased cardiovascular risk in HIV-1-infected adults are incompletely understood, but platelet activation and immune activation leading to a prothrombotic state have been proposed as significant contributors. Aspirin has antiplatelet and immunomodulatory properties. We explored whether 1 week of low-dose aspirin attenuates platelet activation and immune activation in HIV-1-infected and virologically suppressed adults on antiretroviral therapy. Methods:Platelet activation and immune activation were measured in HIV-1-infected subjects virologically suppressed on antiretroviral therapy and controls before and after 1 week of low-dose aspirin. Results:Compared with control subjects, HIV-1-infected subjects had increased platelet activation, as measured by spontaneous platelet aggregation and aggregation in response to adenosine diphosphate, collagen, and arachidonic acid. After aspirin therapy, percent aggregation decreased similarly in both HIV-1-infected and control subjects to all platelet agonists tested except aggregation in response to arachidonic acid, which remained elevated in the HIV-1-infected group. HIV-1-infected subjects exhibited increased markers of T-cell activation (CD38 and HLA-DR) and monocyte activation (sCD14), which decreased after 1 week of aspirin therapy. Moreover, leukocyte responses to Toll-like receptor stimulation were enhanced after 1 week of aspirin therapy. In vitro studies showed that HIV-1 plasma could activate healthy platelets, which in turn activated monocytes, implicating a direct role for activated platelets in immune activation. Conclusions:Our data demonstrate that heightened platelet activation and immune activation in treated HIV-1 disease are attenuated by 1 week of aspirin therapy. Aspirin should be further studied for its antithrombotic and immunomodulatory benefits in treated HIV-1 disease.
Factors affecting the mortality of weaned piglets during commercial transport between farms

Factors affecting the number of weaned piglets found dead after commercial transport between farms were studied by means of multilevel Poisson regression. Information relating to 58,682 piglets during 109 journeys in different EU countries was collected at the end of each journey by means of questionnaires. Overall, 0.07 per cent of all the transported piglets were found dead on arrival, and deaths of piglets were recorded in 13.8 per cent of journeys. The final regression model, which was calculated using the complete records from 105 journeys, included the total duration of the journey, the mean outside temperature during the journey, whether the piglets were fasted before transport, whether drinking water was provided, the type of ventilation in the vehicle and the interaction between journey duration and the mean outside temperature. The duration of the journey and the mean outside temperature showed a significant interaction effect, with a gradual increase in the predicted number of dead piglets with increasing journey duration as the outside temperature increased. Providing the piglets with drinking water and having mechanically assisted ventilation (fans) in the vehicle during the journey significantly reduced the number of deaths, as did fasting the piglets before transport.
Challenges for evolutionary multiobjective optimization algorithms in solving variable-length problems

In recent years, research interests have been paid in solving real-world optimization problems with variable-length representation. For population-based optimization algorithms, the challenge lies in maintaining diversity in sizes of solutions and in designing a suitable recombination operator for achieving an adequate diversity. In dealing with multiple conflicting objectives associated with a variable-length problem, the resulting multiple trade-off Pareto-optimal solutions may inherently have different variable sizes. In such a scenario, the fixed recombination and mutation operators may not be able to maintain large-sized solutions, thereby not finding the entire Pareto-optimal set. In this paper, we first construct multiobjective test problems with variable-length structures, and then analyze the difficulties of the constructed test problems by comparing the performance of three state-of-the-art multiobjective evolutionary algorithms. Our preliminary experimental results show that MOEA/D-M2M shows good potential in solving the multiobjective test problems with variable-length structures due to its diversity strategy along different search directions. Our correlation analysis on the Pareto solutions with variable sizes in the Pareto front indicates that mating restriction is necessary in solving variable-length problem.
Glutathione S-transferase Polymorphisms Are Not Associated With Population Pharmacokinetic Parameters of Busulfan in Pediatric Patients

High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.
Oxidation of hydrogen and reduction of methanol to methane is the sole energy source for a methanogen isolated from human feces

A methanogenic coccus isolated from human feces requires H2 and CH3OH for growth and uses H2 to reduce CH3OH to CH4. Growth does not occur with CH3OH alone. The organism does not grow or produce CH4 from acetate or methylamines without or with H2 or from H2 and CO2 or formate. In a complex medium. CO2 is required for formation of approximately 50% of cell carbon, whereas the methyl carbon from methanol is not incorporated into cell carbon.
Impact of adversity on functioning and comorbidity in children with attention-deficit hyperactivity disorder.

OBJECTIVE Prior research on risk factors for attention-deficit hyperactivity disorder (ADHD) has shown that familial risk factors play a role in the disorder's etiology. This study investigated whether features of the family environment were associated with ADHD. METHOD One hundred forty children with ADHD and 120 normal control probands were studied. Subjects were Caucasian, non-Hispanic males between the ages of 6 and 17 years. Exposure to parental psychopathology and exposure to parental conflict were used as indicators of adversity, and their impact on ADHD and ADHD-related psychopathology and dysfunction in children was assessed. RESULTS Increased levels of environmental adversity were found among ADHD compared with control probands. The analyses showed significant associations between the index of parental conflict and several of the measures of psychopathology and psychosocial functioning in the children. In contrast, the index of exposure to parental psychopathology had a much narrower impact, affecting primarily the child's use of leisure time and externalizing symptoms. CONCLUSIONS A relationship appears to exist between adversity indicators and the risk for ADHD as well as for its associated impairments in multiple domains. These findings confirm previous work and stress the importance of adverse family-environment variables as risk factors for children who have ADHD.
Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta.

OBJECTIVE To study the mechanism by which hypoxia and inflammatory cytokines mediate angiogenesis in the rheumatoid pannus through their effects on the fibroblast-like type B synoviocyte, the major cell type of normal synovia. METHODS Fibroblasts were prepared from synovial tissue of healthy and diseased individuals, and cultured in the presence of various stimuli. The expression of vascular endothelial growth factor (VEGF) was assessed by ELISA and reverse transcription polymerase chain reaction. RESULTS Unlike normal fibroblasts, synovial fibroblasts from rheumatoid arthritis (RA) and osteoarthritis constitutively secreted significant levels of VEGF, which is known to act directly on endothelial cells. VEGF secretion was further inducible by both hypoxia and interleukin 1beta (IL-1beta) and these increases were additive. In contrast, tumor necrosis factor alpha was unable to induce VEGF expression. CONCLUSION Under hypoxia or IL-1 stimulation, conditions common to the inflamed synovium, type B synoviocytes secrete increased levels of VEGF, which is likely to act on nearby endothelia, promoting angiogenesis. The constitutive expression of VEGF in rheumatoid synovial fibroblasts may reflect an altered phenotype involved in the pathology of RA.
Expression of CXCR4 in Eosinophils: Functional Analyses and Cytokine-Mediated Regulation1

We examined the expression of transcripts of a panel of chemokine receptors in human eosinophils and found intense constitutive expression of CXCR4 mRNA. Although surface CXCR4 protein was hardly detectable in the peripheral blood or freshly isolated eosinophils, surface expression of CXCR4 became gradually apparent during incubation at 37°C. In contrast, the level of CCR3 expression was virtually unchanged during the incubation. Stromal cell-derived factor-1α (SDF-1α), the natural ligand of CXCR4, elicited an apparent Ca2+ influx in these cells and induced a strong migratory response comparable to that by eotaxin. The surface expression of CXCR4 in eosinophils was up-regulated by IFN-γ, TNF-α, and TGF-β while it was down-regulated by IL-4 and eosinophil-directed hemopoietins such as IL-5. The CXCR4 expression did not always parallel the apoptotic changes in cytokine-treated eosinophils. In contrast to IL-4 and IFN-γ, IL-5 potently reduced the level of CXCR4 mRNA. It seems unlikely that CXCR4 is fundamentally involved in the pathogenesis of allergic disorders by inducing the migration of eosinophils toward inflammatory sites, because a Th2-dominant state down-regulates eosinophil CXCR4 expression. However, CXCR4 may affect the size of the mobilizable pool by holding eosinophils at noninflamed tissues. Th2-dominant state may favor the liberation of eosinophils by down-regulating CXCR4 expression. The interplay between CXCR4 and SDF-1α in eosinophils potentially plays an important role in the accumulation of these cells at the allergic inflammatory sites.
Molecular and Functional Interdependence of the Urokinase-Type Plasminogen Activator System with Integrins

Abstract The serine protease urokinase-type plasminogen activator (uPA), its inhibitor PAI-1, and its cellular receptor uPA-R (CD87) are of crucial importance during cellular invasion and migration, required for a variety of physio- and pathophysiological processes. It has become increasingly evident in recent years that the uPA/uPA-R-system has far more functional properties than plasminogen activation alone. This is reflected by its involvement in cellular events such as proliferation, adhesion, migration, and chemotaxis. Since uPA-R lacks a transmembrane domain and thus on its own is not capable of transmitting signals into cells, association and functional cooperation with other signaling molecules/receptors is needed. In this respect, one group of adhesion and signaling receptors, the integrins, have been identified which constitute, together with the uPA/uPA-R-system, an interdependent biological network by which the uPA/uPA-R-system broadly affects integrin functions and vice versa. Moreover, there is a growing body of evidence that cellular uPA, uPA-R, and PAI-1 expression is under control of specific ECM/integrin interactions and also that integrins are regulated by components of the uPA/uPARsystem. By this multifaceted crosstalk, cells may modulate their proteolytic, adhesive, and migratory activities and monitor ECM integrity in their microenvironment.
Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2

Benefits on cognition from docosahexaenoic acid (DHA, 22 : 6 n‐3) intake are absent in humans carrying apolipoprotein E ε4 allele (APOE4), the most important genetic risk factor for Alzheimer's disease (AD). To test the hypothesis that carrying APOE4 impairs DHA distribution, we evaluated plasma and brain fatty acid profiles and uptake of [14C]‐DHA using in situ cerebral perfusion through the blood–brain barrier in 4‐ and 13‐month‐old male and female APOE‐targeted replacement mice (APOE2, APOE3, and APOE4), fed with a DHA‐depleted diet. Cortical and plasma DHA were 9% lower and 34% higher in APOE4 compared to APOE2 mice, respectively. Brain uptake of [14C]‐DHA was 24% lower in APOE4 versus APOE2 mice. A significant relationship was established between DHA and apoE concentrations in the cortex of mice (r2 = 0.21) and AD patients (r2 = 0.32). Altogether, our results suggest that lower brain uptake of DHA in APOE4 than in APOE2 mice may limit the accumulation of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of AD.
Fate of the Inner Nuclear Membrane Protein Lamin B Receptor and Nuclear Lamins in Herpes Simplex Virus Type 1 Infection

ABSTRACT During herpesvirus egress, capsids bud through the inner nuclear membrane. Underlying this membrane is the nuclear lamina, a meshwork of intermediate filaments with which it is tightly associated. Details of alterations to the lamina and the inner nuclear membrane during infection and the mechanisms involved in capsid transport across these structures remain unclear. Here we describe the fate of key protein components of the nuclear envelope and lamina during herpes simplex virus type 1 (HSV-1) infection. We followed the distribution of the inner nuclear membrane protein lamin B receptor (LBR) and lamins A and B2 tagged with green fluorescent protein (GFP) in live infected cells. Together with additional results from indirect immunofluorescence, our studies reveal major morphologic distortion of nuclear-rim LBR and lamins A/C, B1, and B2. By 8 h p.i. , we also observed a significant redistribution of LBR-GFP to the endoplasmic reticulum, where it colocalized with a subpopulation of cytoplasmic glycoprotein B by immunofluorescence. In addition, analysis by fluorescence recovery after photobleaching reveals that LBR-GFP exhibited increased diffusional mobility within the nuclear membrane of infected cells. This is consistent with the disruption of interactions between LBR and the underlying lamina. In addition to studying stably expressed GFP-lamins by fluorescence microscopy, we studied endogenous A- and B-type lamins in infected cells by Western blotting. Both approaches reveal a loss of lamins associated with virus infection. These data indicate major disruption of the nuclear envelope and lamina of HSV-1-infected cells and are consistent with a virus-induced dismantling of the nuclear lamina, possibly in order to gain access to the inner nuclear membrane.
Activation of the Raf‐1/MEK/Erk kinase pathway by a novel Cdc25 inhibitor in human prostate cancer cells

The serine/threonine kinase Raf‐1 is a major regulator of the mitogen activated protein kinase (MAPK) pathway, which has been associated with the progression of prostate cancer to the more advanced and androgen‐independent disease. Cdc25A phosphatase has been implicated in the regulation of Raf‐1 and the MAPK pathway.
Segmentation of cytological stained cell areas and generation of cell boundaries in complex shaded cell clusters

In this paper a method is introduced to segment cytological stained cells in microscopic images with the histogram backprojection algorithm (HB). The segmented cell areas are classified in cell clusters and individual cells by a function based on iterative erosion. The cell cores are also segmented with the HB algorithm and the result is modified by image processing functions to get connected areas. The detected cell cores help with the separation of the cells in the clusters. The locations of the waists of the cell clusters are determined by means of so called dominant contour points [5]. At these positions a cell separation makes sense from a biological point of view. The creation of separation lines is carried out by opposing contour points. To find opposing contour points the shortest path between two neighboring cell cores in a cell cluster is calculated by the A*- algorithm [6] and utilizing additional suitable rules.
Idarucizumab, a Humanized, Monoclonal Antibody Fragment for Immediate Reversal of Dabigatran

Objective: To evaluate the role of idarucizumab, a humanized monoclonal antibody fragment, as a specific reversal agent for the anticoagulant activity of dabigatran and to review the pharmacology, pharmacokinetic properties, efficacy, and safety of this agent. Methods: A literature search was conducted consisting of a PubMed database using the MeSH term idarucizumab and the key word dabigatran antidote. Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of idarucizumab for the reversal of the anticoagulant activity of dabigatran were included. Results: Idarucizumab represents a novel treatment option as it is the only humanized, monoclonal antibody fragment that specifically binds to dabigatran. Studies evaluating reversal of dabigatran-induced anticoagulation have demonstrated immediate, complete, and sustained effects with idarucizumab. Idarucizumab did not overcorrect thrombin generation. Additionally, evaluations have shown that dabigatran can be safely reinitiated 24 hours after the administration of idarucizumab. The United States Food and Drug Administration granted priority review for the biologic license application and accelerated approval for idarucizumab. Conclusion: Idarucizumab represents an encouraging development in the reversal of dabigatran. Its novel mechanism of action, pharmacokinetics, tolerability, and lack of thrombotic events contribute positively to its use in patients who experience bleeding or for those who require emergent surgery or procedures.
Screening for Fetal Aneuploidy: Is Maternal Age Relevant?

The process of genetic screening has evolved from a simple notation of maternal age to a complex algorithm incorporating age, maternal serum screening, and sonographic findings. The extent to which each of these variables should contribute to the overall screening result is much debated and deserves continued research. It is clear that maternal age provides useful information when used as part of this equation but should not represent the sole screening modality. The use of genetic screening in a general population should be examined in terms of cost effectiveness without sacrificing patient preference and autonomy.
Predicting the results of reasoning experiments: Reply to Feeney and Handley (2000)

Feeney and Handley (2000) present evidence that they argue is not consistent with Oaksford and Chater’s (1994) information gain model of data selection behaviour in Wason’s (1966, 1968) selection task. They introduced a second rule into the selection task, a manipulation that has revealed interesting results in the conditional inference paradigm (Byrne, 1989; Cummins, 1995; Cummins, Lubart, Alksnis, & Rist, 1991). Along with the task rule, if p then q, participants were provided with an alternative rule, if r then q.Feeney and Handley argued that this manipulation should suppress selection of the not-p and the q cards and only these cards. For example, take the rules if the key is turned (p) the car starts (q) and an alternative rule if the car is hot-wired (r) the car starts (q). Feeney and Handley argue that participants are less likely to look at the not-p card (the key is not turned) because they are now less likely to infer that the car does not start (not-q) because it may have been hot-wired (r). Moreover, they are less likely to look at the q card (the car has started) because they are now less likely to infer that the key was turned (p) because it may have been hot-wired (r). In three experiments Feeney and Handley observed the predicted suppression of not-p and q card selections without any effects on p and not-q card selections (at least in Experiments 2 and 3). According to the information gain model participants’ card selections are determined by the probabilities of the antecedent, P(p), and consequent, P(q). As Feeney and Handley (2000) observe, the introduction of an alternative rule is likely to affect these probabilities because it suggests that P(not-p, q)—for example, the joint probability of cars starting without their ignition keys being turned—is higher. This should not affect P(p): Just making explicit that cars can be started in other ways than by turning the key should have no effect on the frequency of turning the ignition key to start the car. However, it should increase estimates of P(q): The overall incidence of cars starting must increase given alternative methods of achieving this goal.Feeney and Handley argue that in the informationgainmodel this change should affect p, q, and not-q card selections but not not-p card selections. However, they observed effects on only the q and the not-p cards. Consequently they argue that their data are not consistent with
Improving performance of a hyper-heuristic using a multilayer perceptron for vehicle routing

A hyper-heuristic is a heuristic optimisation method which generates or selects heuristics (move operators) based on a set of components while solving a computationally difficult problem. Apprenticeship learning arises while observing the behavior of an expert in action. In this study, we use a multilayer perceptron (MLP) as an apprenticeship learning algorithm to improve upon the performance of a state-of-the-art selection hyper-heuristic used as an expert, which was the winner of a cross-domain heuristic search challenge (CHeSC 2011). We collect data based on the relevant actions of the expert while solving selected vehicle routing problem instances from CHeSC 2011. Then an MLP is trained using this data to build a selection hyper-heuristic consisting of a number classifiers for heuristic selection, parameter control, and move-acceptance. The generated selection hyper-heuristic is tested on the unseen vehicle routing problem instances. The empirical results indicate the success of MLP-based hyper-heuristic achieving a better performance than the expert and some previously proposed algorithms.