Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetic Interactions between Primaquine and Pyronaridine-Artesunate in Healthy Adult Thai Subjects

ABSTRACT Pyronaridine-artesunate is a newly introduced artemisinin-based combination treatment which may be deployed together with primaquine. A single-dose, randomized, three-sequence crossover study was conducted in healthy Thai volunteers to characterize potential pharmacokinetic interactions between these drugs. Seventeen healthy adults received a single oral dose of primaquine alone (30 mg base) and were then randomized to receive pyronaridine-artesunate alone (540−180 mg) or pyronaridine-artesunate plus primaquine in combination, with intervening washout periods between all treatments. The pharmacokinetic properties of primaquine, its metabolite carboxyprimaquine, artesunate, its metabolite dihydroartemisinin, and pyronaridine were assessed in 15 subjects using a noncompartmental approach followed by a bioequivalence evaluation. All drugs were well tolerated. The single oral dose of primaquine did not result in any clinically relevant pharmacokinetic alterations to pyronaridine, artesunate, or dihydroartemisinin exposures. There were significantly higher primaquine maximum plasma drug concentrations (geometric mean ratio, 30%; 90% confidence interval [CI], 17% to 46%) and total exposures (15%; 6.4% to 24%) during coadministration with pyronaridine-artesunate than when primaquine was given alone. Pyronaridine, like chloroquine and piperaquine, increases plasma primaquine concentrations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01552330.)
Cell Cycle-Dependent Mobility of Cdc45 Determined in vivo by Fluorescence Correlation Spectroscopy

Eukaryotic DNA replication is a dynamic process requiring the co-operation of specific replication proteins. We measured the mobility of eGFP-Cdc45 by Fluorescence Correlation Spectroscopy (FCS) in vivo in asynchronous cells and in cells synchronized at the G1/S transition and during S phase. Our data show that eGFP-Cdc45 mobility is faster in G1/S transition compared to S phase suggesting that Cdc45 is part of larger protein complex formed in S phase. Furthermore, the size of complexes containing Cdc45 was estimated in asynchronous, G1/S and S phase-synchronized cells using gel filtration chromatography; these findings complemented the in vivo FCS data. Analysis of the mobility of eGFP-Cdc45 and the size of complexes containing Cdc45 and eGFP-Cdc45 after UVC-mediated DNA damage revealed no significant changes in diffusion rates and complex sizes using FCS and gel filtration chromatography analyses. This suggests that after UV-damage, Cdc45 is still present in a large multi-protein complex and that its mobility within living cells is consistently similar following UVC-mediated DNA damage.
Height process for super-critical continuous state branching process

We define the height process for super-critical continuous state branching processes with quadratic branching mechanism. It appears as a projective limit of Brownian motions with positive drift reflected at 0 and a>0 as a goes to infinity. Then we extend the pruning procedure of branching processes to the super-critical case. This give a complete duality picture between pruning and size proportional immigration for quadratic continuous state branching processes.
Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load

Objective:Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. Design and methods:By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. Results:Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4–6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9–14.9] and 11.4 (95% CI, 7.8–27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4–137.0) and 66.5 (95% CI, 36.7–222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. Conclusion:HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted.
Designing modular services in the scattered byzantine failure model

In this paper, we propose the scattered byzantine failure model. In this model, processes alternate correct and faulty periods. Specifically, during its faulty periods, a process behaves arbitrarily (one cannot expect anything from it during these periods) whereas during its correct periods, it behaves according to its specification. In that sense, the scattered byzantine failure model generalizes the classical Byzantine failure model. We characterize two reliable services guaranteeing timeliness properties in the presence of Byzantine failures, namely the clock synchronization and the /spl delta/-Atomic Broadcast. We identify necessary and sufficient conditions to ensure the correctness of both services in the scattered byzantine failure model.
Host condition and individual risk of cowpox virus infection in natural animal populations: cause or effect?

SUMMARY Recent studies have provided evidence that endemic pathogens may affect dynamics in animals. However, such studies have not typically considered that infected individuals might have a preceding underlying poor condition. We examined whether individuals in poor condition are more likely to become infected by an endemic pathogen, using as a system the dynamics of cowpox virus in field voles. With data from monthly sampled vole populations, a nested case-control study evaluated whether susceptible individuals with poorer condition had higher probabilities of contracting cowpox. The influence of condition was found to be considerable, especially for males. At times when a susceptible male with good body condition had a relatively low probability of becoming infected, a susceptible male with poor body condition was twice as likely to contract cowpox; if this male was also anaemic, the chances were almost quadrupled. We discuss the care needed when interpreting the findings of wildlife disease studies.
Community falls prevention for people who call an emergency ambulance after a fall: an economic evaluation alongside a randomised controlled trial.

OBJECTIVE we estimated the cost-effectiveness of a community falls prevention service compared with usual care from a National Health Service and personal social services perspective over the 12 month trial period. DESIGN a cost-effectiveness and cost utility analysis alongside a randomised controlled trial SETTING community. PARTICIPANTS people over 60 years of age living at home or in residential care who had fallen and called an emergency ambulance but were not taken to hospital. INTERVENTIONS referral to community fall prevention services or usual health and social care. MEASUREMENTS incremental cost per fall prevented and incremental cost per Quality-Adjusted Life Years (QALYs) RESULTS a total of 157 participants (82 interventions and 75 controls) were used to perform the economic evaluation. The mean difference in NHS and personal social service costs between the groups was £-1,551 per patient over 1 year (95% CI: £-5,932 to £2,829) comparing the intervention and control groups. The intervention patients experienced on average 5.34 fewer falls over 12 months (95% CI: -7.06 to -3.62). The mean difference in QALYs was 0.070 (95% CI: -0.010 to 0.150) in favour of the intervention group. CONCLUSION the community falls prevention service was estimated to be cost-effective in this high-risk group. Current Controlled Trials ISRCTN67535605. (controlled-trials.com).
The fibronectin leucine-rich repeat transmembrane protein Flrt2 is required in the epicardium to promote heart morphogenesis

The epicardium, the outermost tissue layer that envelops the developing heart and provides essential trophic signals for the myocardium, derives from the pro-epicardial organ (PEO). Two of the three members of the Flrt family of transmembrane glycoproteins, Flrt2 and Flrt3, are strongly co-expressed in the PEO. However, beginning at around day 10 of mouse development, following attachment and outgrowth, Flrt3 is selectively downregulated, and only Flrt2 is exclusively expressed in the fully delaminated epicardium. The present gene-targeting experiments demonstrate that mouse embryos lacking Flrt2 expression arrest at mid-gestation owing to cardiac insufficiency. The defects in integrity of the epicardial sheet and disturbed organization of the underlying basement membrane closely resemble those described in Flrt3-deficient embryos that fail to maintain cell-cell contacts in the anterior visceral endoderm (AVE) signalling centre that normally establishes the A-P axis. Using in vitro and in vivo reconstitution assays, we demonstrate that Flrt2 and Flrt3 are functionally interchangeable. When acting alone, either of these proteins is sufficient to rescue functional activities in the AVE and the developing epicardium.
The tetraspanin CD9 facilitates MERS-coronavirus entry by scaffolding host cell receptors and proteases

Infection by enveloped coronaviruses (CoVs) initiates with viral spike (S) proteins binding to cellular receptors, and is followed by proteolytic cleavage of receptor-bound S proteins, which prompts S protein-mediated virus-cell membrane fusion. Infection therefore requires close proximity of receptors and proteases. We considered whether tetraspanins, scaffolding proteins known to facilitate CoV infections, hold receptors and proteases together on cell membranes. Using knockout cell lines, we found that the tetraspanin CD9, but not the tetraspanin CD81, formed cell-surface complexes of dipeptidyl peptidase 4 (DPP4), the MERS-CoV receptor, and the type II transmembrane serine protease (TTSP) member TMPRSS2, a CoV-activating protease. This CD9-facilitated condensation of receptors and proteases allowed MERS-CoV pseudoviruses to enter cells rapidly and efficiently. Without CD9, MERS-CoV viruses were not activated by TTSPs, and they trafficked into endosomes to be cleaved much later and less efficiently by cathepsins. Thus, we identified DPP4:CD9:TTSP as the protein complexes necessary for early, efficient MERS-CoV entry. To evaluate the importance of these complexes in an in vivo CoV infection model, we used recombinant Adenovirus 5 (rAd5) vectors to express human DPP4 in mouse lungs, thereby sensitizing the animals to MERS-CoV infection. When the rAd5-hDPP4 vectors co-expressed small RNAs silencing Cd9 or Tmprss2, the animals were significantly less susceptible, indicating that CD9 and TMPRSS2 facilitated robust in vivo MERS-CoV infection of mouse lungs. Furthermore, the S proteins of virulent mouse-adapted MERS-CoVs acquired a CD9-dependent cell entry character, suggesting that CD9 is a selective agent in the evolution of CoV virulence.
Content-purport, content-substance and structure: focusing mere and merely

Abstract Starting from Hjelmslev’s distinction between content-purport and content-substance, we investigate the meaning of focus markers mere and merely from a diachronic perspective. We argue that their shared ability to convey the four focus types (exclusive-categorial, exclusive-scalar, particularizing, inclusive) can be viewed as their shared content-purport. We approach their content-substance, i.e. the meanings coded by their structures, in terms of the interpersonal modification structures of McGregor’s Semiotic Grammar. The different syntagmatic combinations are associated with different contextual usage types.
Introspection of complex cognitive processes

In the last decade, there has been a huge effort in cognitive science devoted to the understanding of how individuals access their own cognitive productions. This thesis investigates which mental contents are accessible by introspection. Four experimental projects were developed. The first project investigates the possibility to introspectively access and discriminate complex cognitive processes in the context of a visual search paradigm (serial searches vs. parallel searches). The second project refines the results of the first project. We used a pre-conscious visual cue to alter a visual search, and collected introspective data showing that participants were sensitive to this alteration. The results in both projects converge on three main ideas: 1) introspection is capable of accessing complex cognitive processes; 2) introspection is permeable to different sources of information underlying the experimental task; 3) the focus of introspection can be experimentally controlled during a simple cognitive task. The third project extends the results evidenced in projects 1 and 2 to another domain: working memory. The study shows that introspection can successfully access the type of cognitive process engaged during memory recovery (serial access to information vs. parallel access). Lastly, the fourth project investigates an individual factor that might alter the precision of introspective reports: biological reactivity to stress. Results indicated that individuals with high reactivity to stress have a poorer introspective access of their mental states. The present thesis presents a first systematic account of the functional architecture of introspective report.
Examining User Acceptance of Mobile Services

Incentives may affect users' behavior. It is critical to study how users' perception and intention are affected by the incentives. This study presents an extended technology acceptance model (TAM) that integrates incentives into TAM to investigate what determines user mobile commerce acceptance. We apply this model to the case of a GPS-based taxi-dispatching system. Preliminary data analysis illustrates that TAM model is fit for mobile technology adoption, and incentives have significant impact on users' behavior.
Mitochondrial DNA sequence variation among geographical isolates of Opisthorchis viverrini in Thailand and Lao PDR, and phylogenetic relationships with other trematodes

SUMMARY The present study compared the genetic variation among 14 different geographical isolates of Opisthorchis viverrini sensu lato from Thailand and Lao PDR using sequence data for 2 mitochondrial DNA genes, the subunit 1 of NADH dehydrogenase gene (nad1) and cytochrome c oxidase gene (cox1). Four different nad1 haplotypes were detected among isolates, all of which were identical at the amino acid sequence level. Nucleotide sequence variation among 14 isolates ranged from 0 to 0·3% for nad1. Two different cox1 haplotypes were detected among isolates. These two haplotypes differed at 2 nucleotide positions, one of which resulted in a change in the amino acid sequence. Nucleotide sequence variation among isolates for cox1 ranged from 0 to 0·5%. Comparison of cox1 sequences of O. viverrini to those of other trematodes revealed nucleotide differences of 13–31%. A phylogenetic analysis of the cox1 sequence data revealed strong statistical support for a clade containing O. viverrini and 2 other species of opisthorchid trematodes; O. felineus and Clonorchis sinsensis.
Expression of the Iron Hormone Hepcidin Distinguishes Different Types of Anemia in African Children

The iron hormone hepcidin correctly identifies African children in whom iron supplementation is most likely to be beneficial. Hepcidin Guides Iron Supplementation in African Children Anemia affects 300 million preschool children worldwide and has multiple causes including iron deficiency or infection. Dietary iron supplementation is used to combat anemia, but substantial concerns exist that iron can be harmful, in part by promoting infection. Iron is likely to preferentially benefit children with iron deficiency anemia, but identification of such children is challenging. Hepcidin is the hormone that regulates body iron levels and inhibits absorption of iron from the diet. Hepcidin concentrations are generally low in iron deficiency but are raised in iron-replete individuals and are also increased by infection. In a new study, Pasricha et al. set out to investigate whether hepcidin measurements would enable targeting of interventions to children who need iron but who are also able to absorb it. They tested this by measuring hepcidin in three cohorts of preschool African children from The Gambia and Tanzania. Single cutoffs of hepcidin concentrations efficiently identified children with iron deficiency, distinguished between iron deficiency anemia and anemia due to infection and inflammation, and predicted which children would incorporate >20% of an oral iron dose into their red blood cells. Thus, hepcidin is a critical determinant of iron homeostasis and may be a useful marker to guide diagnosis of anemia and enable screen-and-treat iron supplementation programs. Childhood anemia is a major global health problem resulting from multiple causes. Iron supplementation addresses iron deficiency anemia but is undesirable for other types of anemia and may exacerbate infections. The peptide hormone hepcidin governs iron absorption; hepcidin transcription is mediated by iron, inflammation, and erythropoietic signals. However, the behavior of hepcidin in populations where anemia is prevalent is not well established. We show that hepcidin measurements in 1313 African children from The Gambia and Tanzania (samples taken in 2001 and 2008, respectively) could be used to identify iron deficiency anemia. A retrospective secondary analysis of published data from 25 Gambian children with either postmalarial or nonmalarial anemia demonstrated that hepcidin measurements identified individuals who incorporated >20% oral iron into their erythrocytes. Modeling showed that this sensitivity of hepcidin expression at the population level could potentially enable simple groupings of individuals with anemia into iron-responsive and non–iron-responsive subtypes and hence could guide iron supplementation for those who would most benefit.
Phasic, Nonsynaptic GABA-A Receptor-Mediated Inhibition Entrains Thalamocortical Oscillations

GABA-A receptors (GABA-ARs) are typically expressed at synaptic or nonsynaptic sites mediating phasic and tonic inhibition, respectively. These two forms of inhibition conjointly control various network oscillations. To disentangle their roles in thalamocortical rhythms, we focally deleted synaptic, γ2 subunit-containing GABA-ARs in the thalamus using viral intervention in mice. After successful removal of γ2 subunit clusters, spontaneous and evoked GABAergic synaptic currents disappeared in thalamocortical cells when the presynaptic, reticular thalamic (nRT) neurons fired in tonic mode. However, when nRT cells fired in burst mode, slow phasic GABA-AR-mediated events persisted, indicating a dynamic, burst-specific recruitment of nonsynaptic GABA-ARs. In vivo, removal of synaptic GABA-ARs reduced the firing of individual thalamocortical cells but did not abolish slow oscillations or sleep spindles. We conclude that nonsynaptic GABA-ARs are recruited in a phasic manner specifically during burst firing of nRT cells and provide sufficient GABA-AR activation to control major thalamocortical oscillations.
SNOBFIT -- Stable Noisy Optimization by Branch and Fit

The software package SNOBFIT for bound-constrained (and soft-constrained) noisy optimization of an expensive objective function is described. It combines global and local search by branching and local fits. The program is made robust and flexible for practical use by allowing for hidden constraints, batch function evaluations, change of search regions, etc.
Journal of Personality and Social Psychology When Matching up Features Messes up Decisions: the Role of Feature Matching in Successive Choices

Two studies examined feature matching in successive judgments. College students in both studies read about 2 apartments with shared positive and unique negative features, and 1 less globally positive apartment with all unique features. In the feature-cancellation condition, participants first saw the shared-features apartments together and then saw the all-unique apartment. In the no-cancellation condition, participants first saw 1 shared-features apartment and the all-unique apartment together and then saw the other shared-features apartment. Shared-features apartments were rated higher when they were not seen together. The all-unique apartment was rated higher when it was seen last, when the first 2 apartments' shared features canceled out. Study 2 replicated Study 1 and also demonstrated that 2 additional variables failed to moderate the effect. Memory measures suggest that shared features are paired up as an organizational strategy. During the 1992 U.S. Presidential election, the country let out a collective whine when presented with the Democratic and Republican candidates. Instead of just expressing the usual apathy about the election, voters seemed actively critical of both of the front-runners. George Bush was seen as being out of touch with middle-and lower-class Americans, too concerned with remote international affairs, and responsible for the coun-try's domestic and economic problems. Bill Clinton was disliked for a different reason: allegations of sins in the past (extramarital affairs, drug use, and draft dodging), which he avoided facing directly in his inimitable "Slick Willy" style. The choice between the two candidates was painted as a decision between the lesser of two evils, and the many overlapping positive qualities of the two front-runners seemed largely ignored. Both were tall, White, male, Ivy League graduates with a great deal of political experience, and both were quite moderate and mainstream , but voters seemed to pay little attention to these similar positive qualifications and instead largely focused on the divisive negative features of Bush and Clinton. Enter third-party candidate Ross Perot, who, despite a dearth of experience in politics, was embraced by Americans as no other third-party candidate had been in recent elections. Clearly, Perot's campaign had a number of advantages, many of them related to his great wealth, but one less obvious help may have been Perot's late entry into a race that already contained two This article is based on my doctoral dissertation, submitted to the University of Virginia. I warmly acknowledge my dissertation committee , headed Electronic mail may be sent …