Miracle-dz/UniFAR-FTUs huggingface dataset:
Strategy to Control Type I Error Increases Power to Identify Genetic Variation Using the Full Biological Trajectory

Genome‐wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear‐mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis‐free genome‐wide setting and recommend its use for genome‐wide studies employing linear‐mixed effects models.
Both CD4+CD25+ and CD4+CD25− Regulatory Cells Mediate Dominant Transplantation Tolerance1

CD4+CD25+ T cells have been proposed as the principal regulators of both self-tolerance and transplantation tolerance. Although CD4+CD25+ T cells do have a suppressive role in transplantation tolerance, so do CD4+CD25− T cells, although 10-fold less potent. Abs to CTLA-4, CD25, IL-10, and IL-4 were unable to abrogate suppression mediated by tolerant spleen cells so excluding any of these molecules as critical agents of suppression. CD4+CD25+ T cells from naive mice can also prevent rejection despite the lack of any previous experience of donor alloantigens. However, this requires many more naive than tolerized cells to provide the same degree of suppression. This suggests that a capacity to regulate transplant rejection pre-exists in naive mice, and may be amplified in “tolerized” mice. Serial analysis of gene expression confirmed that cells sorted into CD4+CD25+ and CD4+CD25− populations were distinct in that they responded to TCR ligation with very different programs of gene expression. Further characterization of the differentially expressed genes may lead to the development of diagnostic tests to monitor the tolerant state.
Understanding gene regulatory mechanisms by integrating ChIP-seq and RNA-seq data: statistical solutions to biological problems

The availability of omic data produced from international consortia, as well as from worldwide laboratories, is offering the possibility both to answer long-standing questions in biomedicine/molecular biology and to formulate novel hypotheses to test. However, the impact of such data is not fully exploited due to a limited availability of multi-omic data integration tools and methods. In this paper, we discuss the interplay between gene expression and epigenetic markers/transcription factors. We show how integrating ChIP-seq and RNA-seq data can help to elucidate gene regulatory mechanisms. In particular, we discuss the two following questions: (i) Can transcription factor occupancies or histone modification data predict gene expression? (ii) Can ChIP-seq and RNA-seq data be used to infer gene regulatory networks? We propose potential directions for statistical data integration. We discuss the importance of incorporating underestimated aspects (such as alternative splicing and long-range chromatin interactions). We also highlight the lack of data benchmarks and the need to develop tools for data integration from a statistical viewpoint, designed in the spirit of reproducible research.
Comparison of direct microscopy and culture in the diagnosis of trichomoniasis.

'The discovery of the growing spread of trichomoniasis is due to improved methods of research. Increased morbidity has accompanied inadequate treatment and is especially due to the confused view of the problem, which is a joint task for gynaecologists, venereologists, and urologists. It may be described as a venereal disease because it is transmitted in the great majority of cases by sexual intercourse. It is so widespread and causes so much ill-health among young women that it is becoming an important social problem. It is necessary to treat both men and women to eliminate the parasite from its inner- most hiding places. '
Quasi-Structural Estimation of a Model of Child Care Choices and Child Cognitive Production

This paper evaluates the effects of maternal time inputs and alternative providers’ time inputs on children’s cognitive development using the sample of single mothers in the National Longitudinal Survey of Youth. In order to deal with the selection problem that arises because of unobserved heterogeneity of mothers and children, we develop a model of mother’s employment and child-care decisions. Guided by this model, we obtain approximate decisions rules for employment and child care use, and estimate these jointly with the child’s cognitive ability production function – an approach we refer to as “quasi-structural. ” We take advantage of the plausibly exogenous variation in employment and child-care choices generated by the differences in welfare regulations across states and over time introduced by the welfare reform legislation of 1996, and prior to that by Section 1115 Welfare Waivers, to help identify the selection model. These welfare rules provide natural exclusion restrictions, as it is plausible that they enter the decision rules for employment and day care use, while not entering the child cognitive ability production function directly. The instruments are quite powerful, in the sense that they explain a substantial part of the variation in work and day care use by single mothers. Our results imply that if a mother works full-time, while placing a child in day care, for one full year, this reduces the child’s cognitive ability test score by 3.0%, which is 0.135 standard deviations. The result we obtain here is very similar to what we obtained in Bernal and Keane (2005), where we adopted a single equation instrumental variable (IV) approach. There, our estimates implied that one year of full-time work and day care use would lower a child’s test scores by 2.9%. Each approach relies on somewhat different identifying assumptions. Thus, it is comforting that results are so robust across the two approaches. 1 Corresponding author: rbernal@northwestern.edu
Inhibitors of HIV-1 Reverse Transcriptase—Associated Ribonuclease H Activity

HIV-1 enzyme reverse transcriptase (RT) is a major target for antiviral drug development, with over half of current FDA-approved therapeutics against HIV infection targeting the DNA polymerase activity of this enzyme. HIV-1 RT is a multifunctional enzyme that has RNA and DNA dependent polymerase activity, along with ribonuclease H (RNase H) activity. The latter is responsible for degradation of the viral genomic RNA template during first strand DNA synthesis to allow completion of reverse transcription and the viral dsDNA. While the RNase H activity of RT has been shown to be essential for virus infectivity, all currently used drugs directed at RT inhibit the polymerase activity of the enzyme; none target RNase H. In the last decade, the increasing prevalence of HIV variants resistant to clinically used antiretrovirals has stimulated the search for inhibitors directed at stages of HIV replication different than those targeted by current drugs. HIV RNase H is one such novel target and, over the past few years, significant progress has been made in identifying and characterizing new RNase H inhibitor pharmacophores. In this review we focus mainly on the most potent low micromolar potency compounds, as these provide logical bases for further development. We also discuss why HIV RNase H has been a difficult target for antiretroviral drug development.
Fault analysis of an islanded Multi-microgrid

A microgrid (MG) is one way of integrating several low capacity renewable energy sources with a distribution grid. Multi-microgrids (MMG) originally proposed by the EU More Microgrids project can combine several MGs along with other distributed generation (DG) sources into the distribution grid. While different aspects of MMGs have been previously studied, a protection system design for it is yet to be explored. To design protection systems for MMGs, it is first necessary to study their fault characteristics. In this paper, we report on the fault analysis of an MMG consisting of two MGs, each made up of a diesel generator and a number of PV sources and wind generators. Fault analysis is carried out by simulating different fault types in the MMG with the distribution grid islanded from the transmission grid, and compared with fault currents in a single islanded MG. A theoretical analysis is also performed to verify the simulation results. The fault analysis results can be used to configure relay settings and to select the most appropriate circuit breakers and measurement devices for the MMG.
Outpatient continuous intravenous interleukin-2 or subcutaneous, polyethylene glycol-modified interleukin-2 in human immunodeficiency virus-infected patients: a randomized, controlled, multicenter study. Australian IL-2 Study Group.

The safety and activity of outpatient-based continuous intravenous interleukin-2 (CIV IL-2) or a slow-release, polyethylene glycol (PEG)-modified IL-2 were studied in human immunodeficiency virus (HIV)-infected persons with CD4 cell counts between 200 and 500/mm3. One hundred fifteen patients were randomized to antiretroviral therapy plus cyclical CIV IL-2 (n = 27), subcutaneous PEG IL-2 (n = 58), or no IL-2 (n = 30). Toxicity withdrawal rates were low (4% for CIV IL-2 and 7% for PEG IL-2). There were median CD4 cell count increases of 359 and 44 cells/mm3 and a decline of 46 cells/mm3 in the 3 groups, respectively, over 1 year (P < .0001 for each intergroup comparison). CD4 cell count increases were greatest in those with lower HIV RNA load. Delayed-type hypersensitivity scores increased and HLA-DR expression on CD8 cells decreased significantly with IL-2 therapy. HIV RNA levels were unaffected. IL-2 therapy may expand the existing immune repertoire but not immediately reconstitute lost immune function.
Dielectric properties and electrical switching behaviour of the spin-driven multiferroic LiCuVO4

The simultaneous existence and coupling of ferroelectric and magnetic ordering in a material, so-called multiferroicity, is of great scientific interest due to the underlying complex physical mechanisms and its possible applications. Here we present the multiferroic properties of a prototypical spin-driven ferroelectric material, the spin-1/2 chain cuprate LiCuVO4. In this system, spiral spin order, with propagation in the b direction and a spin helix in the ab plane, induces ferroelectric polarization in the a direction when no magnetic field is applied. In an external magnetic field, the direction of the spin spiral and thus the direction of the electrical polarization can be switched. Broadband dielectric spectroscopy on a single crystalline sample oriented in two different directions was performed in applied external magnetic fields up to 9 T, demonstrating this switching behaviour of the ferroelectric polarization. Furthermore, detailed magnetic-field and temperature-dependent ferroelectric hysteresis-loop measurements reveal the switching of polarization by an electrical field, which implies the electric control of the spin helicity of LiCuVO4.
SEQATOMS: a web tool for identifying missing regions in PDB in sequence context

With over 46 000 proteins, the Protein Data Bank (PDB) is the most important database with structural information of biological macromolecules. PDB files contain sequence and coordinate information. Residues present in the sequence can be absent from the coordinate section, which means their position in space is unknown. Similarity searches are routinely carried out against sequences taken from PDB SEQRES. However, there no distinction is made between residues that have a known or unknown position in the 3D protein structure. We present a FASTA sequence database that is produced by combining the sequence and coordinate information. All residues absent from the PDB coordinate section are masked with lower-case letters, thereby providing a view of these residues in the context of the entire protein sequence, which facilitates inspecting ‘missing’ regions. We also provide a masked version of the CATH domain database. A user-friendly BLAST interface is available for similarity searching. In contrast to standard (stand-alone) BLAST output, which only contains upper-case letters, our output retains the lower-case letters of the masked regions. Thus, our server can be used to perform BLAST searching case-sensitively. Here, we have applied it to the study of missing regions in their sequence context. SEQATOMS is available at http://www.bioinformatics. nl/tools/seqatoms/.
Can Videogames be Addicting? An Investigation into the Specific Game Features and Personal Characteristics Associated with Problematic Videogame Playing

The number of individuals who play videogames has increased dramatically in recent years. Unsurprisingly, the frequency with which patients seek psychotherapeutic services to help cope with problematic videogame playing (PVGP) behaviors has also risen. Thus, explorations into the specific characteristics of PVGP are essential now more than ever before. However, the current state of the literature primarily relies on comparisons between PVGP and pathological gambling, utilizing modified measures of the latter to assess the former. To date, no studies have attempted to adapt the diagnostic criteria for substance use disorder (SUD) in an effort to understand PVGP within the context of addiction. Further, few studies have explored the specific game characteristics and individual factors that contribute to the presence of PVGP. The current study sought to address these questions by adapting the SUD criteria to address videogame-related behavior via a measure labeled as the Videogame Addiction Scale (VGAS). Comparisons of the psychometrics and criterion validity of the VGAS and leading measures of PVGP suggested the former was superior. Further, results indicated that higher levels of addiction were present in players who prefer the MMORPG and Shooter genres over all other types of games, with the former yielding significantly higher VGAS scores than the latter. Further, many of the structural characteristics of videogames were considered to be more enjoyable, important, and associated with longer playtimes for individuals with higher “addiction” scores than their low scoring counterparts. Lastly, a model of videogame addiction was generated that aligns with the current literature on substance use disorders. Specifically, impulsivity, maladaptive coping, weekly playtime, and particular structural characteristics all seem to relate to videogame addiction. Videogames and Addiction iii
The abundances of nitrogen-containing molecules during pre-protostellar collapse

Aims. We have studied the chemistry of nitrogen-bearing species during the initial stages of protostellar collapse, with a view to explaining the observed longevity of N 2 H + and NH 3 and the high levels of deuteration of these species. Methods. We followed the chemical evolution of a medium comprising gas and dust as it underwent free-fall gravitational collapse. Chemical processes which determine the relative populations of the nuclear spin states of molecules and molecular ions were included explicitly, as were reactions which lead ultimately to the deuteration of the nitrogen-containing species N 2 H + and NH 3 . The freeze-out of "heavy" molecules on to dust grains was taken into account. Results. We found that the timescale required for the nitrogen-containing species to attain their steady-state values was much larger than the free-fall time and even comparable with the probable lifetime of the precursor molecular cloud. However, it transpires that the chemical evolution of the gas during gravitational collapse is insensitive to its initial composition. If we suppose that the grain-sticking probabilities of atomic nitrogen and atomic oxygen are both less than unity (S ≤ 0.3), we find that the observed differential freeze-out of nitrogen- and carbon-bearing species can be reproduced by the model of free-fall collapse when a sufficiently large grain radius (a g ≈ 0.50 μm) is adopted. Furthermore, the results of our collapse model are consistent with the high levels of deuteration of N 2 H + and NH 3 which have been observed in L1544, for example, providing that 0.5 ≤ ag ≤ 1.0 μm. We note that the ortho:para H 2 D + ratio, and fractional abundance of ortho-H 2 D + , which is the observed form of H 2 D + , should be largest where ND 3 is most abundant.
Analysis of relation between hypoxia PET imaging and tissue-based biomarkers during head and neck radiochemotherapy

Abstract Background: Tumor hypoxia is associated with poor prognosis and outcome and can be visualized using 18F-MISO-positron emission tomography (PET) imaging. The goal of this study was to evaluate the correlation between biological markers and biological imaging in a group of patients in whom a correlation between biological imaging and outcome has previously been demonstrated. Material and methods: In a prospective pilot project, 16 patients with locally advanced cancer of the head and neck underwent 18F-MISO-PET scans before and during primary radiochemotherapy in addition to 18F-FDG-PET and computed tomography (CT). Tumor biopsies were stained for three tissue-based markers (Ku80, CAIX, CD44); in addition, human papillomavirus (HPV) status was assessed. H-scores of marker expression were generated and the results were correlated with the biological imaging and clinical outcome. Results: No statistically significant correlation was established between the H-scores for Ku80, CD44 and CAIX or between any of the H-scores and the imaging variables (tumor volume on 18F-FDG-PET in ml, hypoxic subvolume as assessed by 18F-MISO-PET in ml, and SUVmax tumor/SUVmean muscle during the 18F-MISO-PET). A statistically significant negative correlation was found between CD44 H-score and HPV status (p = .004). Cox regression analysis for overall survival and recurrence-free survival showed one significant result for CAIX being associated with improved overall survival [hazard ratio 0.96 (0.93–1.00), p = . 047]. Conclusion: Expression of Ku80, CAIX and CD44 as assessed by immunohistochemistry of tumor biopsies were not correlated to one another or the biological imaging data. However, there was a significant influence of CAIX on overall survival and between CD44 and HPV.
Characteristics of multiple voltage‐activated K+ currents in acutely dissociated chick ciliary ganglion neurones.

1. The properties of voltage‐activated K+ currents were examined using whole‐cell recording techniques in acutely isolated chick ciliary ganglion neurones. 2. Application of depolarizing voltage pulses from a holding potential of ‐60 mV evoked sustained outward currents that inactivated with time constants of hundreds of milliseconds (IDR). Bath application of 10 mM tetraethylammonium (TEA) caused a 70‐90% reduction of IDR. Application of depolarizing voltage steps from a holding potential of ‐120 mV revealed a second class of TEA‐resistant outward currents. These currents activated quickly but inactivated completely within tens of milliseconds (IA). IA activated at more negative command potentials than IDR. However, IDR exhibited a steeper voltage dependence of activation than IA. 3. The midpoint of the steady‐state inactivation curve of IA was between ‐95 and ‐110 mV. By contrast the midpoint of the steady‐state inactivation curve of IDR was between ‐80 and ‐90 mV. It was not possible to produce a complete inactivation of IDR using prepulses of up to 2 s duration. 4. The time course of IA inactivation could only be fitted with double‐exponential curves with time constants of 5‐18 ms and 30‐60 ms at membrane potentials positive to ‐30 mV. The inactivation of IA was slower at more positive membrane potentials because of a greater contribution of the long time constant. The individual time constants were not markedly voltage dependent. 5. Bath application of 5 mM 4‐aminopyridine (4‐AP) caused a 70‐100% block of IA whereas 1 mM 4‐AP was ineffective. Bath application of 560 nM alpha‐dendrotoxin (DTX) produced a 50‐70% reduction of IA, but application of 280 nM DTX had no effect on IA. 6. Application of 1 mM 4‐AP produced a reversible 55‐80% block of IDR measured at the end of a 500 ms depolarizing pulse. The 4‐AP‐sensitive components of IDR activated rapidly and exhibited a gradual inactivation with continued depolarization. The 4‐AP‐resistant components of IDR activated much more slowly and showed very little tendency to inactivate. Significant blockade of IDR was produced by 10 microM 4‐AP. 7. The decay of IDR tail currents could only be fitted with double exponential curves with time constants of 3‐6 and 40‐60 ms, respectively. The fast and slow components of the tail currents behaved independently with respect to the duration of the depolarizing voltage step. 8. Application of 1 mM 4‐AP eliminated the fast, but not the slow component of IDR tail currents. (ABSTRACT TRUNCATED AT 400 WORDS)
Empiric Combination Therapy for Gram-Negative Bacteremia

BACKGROUND: Empirical combination antibiotic regimens consisting of a β-lactam and an aminoglycoside are frequently employed in the pediatric population. Data to demonstrate the comparative benefit of empirical β-lactam combination therapy relative to monotherapy for culture-proven Gram-negative bacteremia are lacking in the pediatric population. METHODS: We conducted a retrospective cohort study of children treated for Gram-negative bacteremia at The Johns Hopkins Hospital from 2004 through 2012. We compared the estimated odds of 10-day mortality and the relative duration of bacteremia for children receiving empirical combination therapy versus empirical monotherapy using 1:1 nearest-neighbor propensity-score matching without replacement, before performing regression analysis. RESULTS: We identified 226 matched pairs of patients well balanced on baseline covariates. Ten-day mortality was similar between the groups (odds ratio, 0.84; 95% confidence interval [CI], 0.28 to 1.71). Use of empirical combination therapy was not associated with a decrease in the duration of bacteremia (−0.51 days; 95% CI, −2.22 to 1.48 days). There was no survival benefit when evaluating 10-day mortality for the severely ill (pediatric risk of mortality III score ≥15) or profoundly neutropenic patients (absolute neutrophil count ≤100 cells/mL) receiving combination therapy. However, a survival benefit was observed when empirical combination therapy was prescribed for children growing multidrug-resistant Gram-negative organisms from the bloodstream (odds ratio, 0.70; 95% CI, 0.51 to 0.84). CONCLUSIONS: Although there appears to be no advantage to the routine addition of an aminoglycoside to a β-lactam as empirical therapy for children who have Gram-negative bacteremia, children who have risk factors for MDRGN organisms appear to benefit from this practice.