Miracle-dz/UniFAR-FTUs huggingface dataset:
On the Observed Large Interspecies Overprediction of Human Clearance (“Vertical Allometry”) of UCN‐01: Further Support for a Proposed Model Based on Plasma Protein Binding

The prediction of a human clearance (CL) value for UCN‐01, an extreme example of vertical allometry (a large overprediction by allometric scaling), was examined using commonly used simple allometry and the “rule of exponents,” as well as a newly proposed model, which quantitatively incorporates plasma protein‐binding information from rats and humans. Simple allometry and the rule of exponents were shown to overpredict the human CL value of UCN‐01 by about 5000‐ and 1750‐fold, respectively. The new model incorporating the ratio of fraction unbound between rats and humans improved the prediction by about 20‐fold compared to the rule of exponents. The model is expected to improve if a more accurate measurement of the unbound fraction in human plasma is obtained. The prediction of volume distribution for UCN‐01 by allometric scaling was also shown to be dependent on the difference of fraction unbound between animal species and humans. In summary, plasma protein binding has been demonstrated to be an important measure for interspecies scaling of pharmacokinetics.
The Specific Monomer/Dimer Equilibrium of the Corticotropin-releasing Factor Receptor Type 1 Is Established in the Endoplasmic Reticulum

Background: GPCRs may be expressed in a monomer/dimer equilibrium at the plasma membrane. Results: For the dimeric CRF1R, we found a constant monomer/dimer equilibrium not only at the plasma membrane but also in the ER. Conclusion: The monomer/dimer equilibrium of the CRF1R is established already in the ER. Significance: Our findings shed new light on the monomer/dimer equilibrium of GPCRs and on ER functions. G protein-coupled receptors (GPCRs) represent the most important drug targets. Although the smallest functional unit of a GPCR is a monomer, it became clear in the past decades that the vast majority of the receptors form dimers. Only very recently, however, data were presented that some receptors may in fact be expressed as a mixture of monomers and dimers and that the interaction of the receptor protomers is dynamic. To date, equilibrium measurements were restricted to the plasma membrane due to experimental limitations. We have addressed the question as to where this equilibrium is established for the corticotropin-releasing factor receptor type 1. By developing a novel approach to analyze single molecule fluorescence cross-correlation spectroscopy data for intracellular membrane compartments, we show that the corticotropin-releasing factor receptor type 1 has a specific monomer/dimer equilibrium that is already established in the endoplasmic reticulum (ER). It remains constant at the plasma membrane even following receptor activation. Moreover, we demonstrate for seven additional GPCRs that they are expressed in specific but substantially different monomer/dimer ratios. Although it is well known that proteins may dimerize in the ER in principle, our data show that the ER is also able to establish the specific monomer/dimer ratios of GPCRs, which sheds new light on the functions of this compartment.
Integrins Regulate Rac Targeting by Internalization of Membrane Domains

Translocation of the small GTP-binding protein Rac1 to the cell plasma membrane is essential for activating downstream effectors and requires integrin-mediated adhesion of cells to extracellular matrix. We report that active Rac1 binds preferentially to low-density, cholesterol-rich membranes, and specificity is determined at least in part by membrane lipids. Cell detachment triggered internalization of plasma membrane cholesterol and lipid raft markers. Preventing internalization maintained Rac1 membrane targeting and effector activation in nonadherent cells. Regulation of lipid rafts by integrin signals may regulate the location of membrane domains such as lipid rafts and thereby control domain-specific signaling events in anchorage-dependent cells.
Simple method for measuring phase transfer functions of transducers

The impulse response of a transducer can be represented in the frequency domain by its complex analog, the transfer function. The amplitude transfer function is measured regularly in contrast to the phase transfer function (PTF). Applications for the PTF range from adjusting the emitted pulse shape for coding based imaging to the optimization of ultrasound contrast imaging methods based on destructive interference. A number of acoustic methods to measure a transducer's PTF exists, but they usually require accurate distance and acoustic wave speed measurements. Small discrepancies in these cause large phase errors. We present a pulse-echo method to measure a transducer's PTF without needing a measurement of the wave travel distance and speed. We generalize it to rectangular transducers. In our method the transducer is excited by a monofrequency sine burst with a rectangular envelope. The transducer initially vibrates at resonance (transient regime) prior to the forcing frequency (steady state regime). The PTF value of the system is the difference between the phases deduced from the transient and the steady state regimes at different forcing frequencies. As the PTF is calculated from a relative difference measuring the wave travel distance or speed is unnecessary. The approach assumes linear wave propagation and uses a pulse-echo setup. The method was tested on a custom built single element transducer (square: 13 × 13 mm, center frequency 4 MHz, no backing or matching layers). The results were compared with KLM model simulations. Also, we phase calibrated a hydrophone, which was then used to measure the PTF of the square transducer. The simulated and measured resonance frequencies differed by 0.17 MHz. The mean PTF difference between simulation and measurements was 7°–14°. The method's reproducibility was ±15°. The PTF of the transducer was measured with good reproducibility, without measuring the wave travel distance or speed of sound in the medium. Our simple setup requires basic laboratory ultrasound equipment.
Weighted Fisher Non-negative Matrix Factorization for Face Recognition

In this paper, we extend the Fisher Non-negative Matrix Factorization (FNMF) to Weighted FNMF (WFNMF). The goal of this technique is to improve the performance of FNMF-based face recognition method under varying expressions, varying illumination, and especially for the case of partial occlusions. An objective function is defined by incorporating weighting into the cost of FNMF decomposition in order to emphasize parts of the data matrix to be approximated. Weighted iterative scheme is derived from FNMF algorithm by incorporating weights into the FNMF update rules. In particular, When applied to face recognition, WFNMF employed a face-centered weighting function in order that as many discriminate features as possible at the center of faces are extracted. Experimental results are presented to compare WFNMF with the FNMF, LNMF, NMF and PCA methods for face recognition, which demonstrates advantages of WFNMF.
Noninvasive estimation of cardiac output

A noninvasive method of measuring cardiac output is described. The method uses adaptive aorta models in conjunction with femoral and carotid pulse contour waveform measurements to calculate aortic flow. Results are presented from measurements on dogs using internal pressure recordings made with fluid-filled catheters and compared with electromagnetic flow measurements taken in the ascending aorta. Preliminary results using external pulse measurements on patients are also presented and compared with thermal dilution measurements. <<ETX>>
Algebraic Decomposition of the TU Wave Morphology Patterns

In principle, the T wave results from the differences in durations of action potentials (AP) of different ventricular regions. Based on this concept, a mathematical model has been developed that represents the TU wave morphology as a summation of four AP‐like functions: TU= S1 ‐ S2 + L1 ‐ L2. The sigmoidal shape of AP‐like curves is produced by Hill's equation V(t) = a · tn/(bn+ tn). Each of the decomposition functions is characterized by two parameters: the amplitude at the beginning of QRS (Amax), and the duration at 5% of Amax (D95). The set of four decomposition functions leads to eight parameters that provide detailed characteristics of the TU wave morphology. The model was validated using 170 TU wave complexes recorded digitally in leads V2‐V6 from 22 normal subjects and 12 patients with abnormal TU wave morphologies (negative, biphasic, and notched T waves). The electrocardiographic signals were sampled at 100 Hz and a best‐fit procedure was used to obtain the decomposition. In all cases the coefficients of correlation between original TU patterns and their mathematical models were ≥ 0.99. The mean absolute difference between the observed and modeled values of the TU patterns was similar in cases with normal and abnormal TU wave morphologies (4.65±0.41 μV vs 5.19±0.48 μV, respectively) demonstrating that the model is capable of describing and categorizing various TU patterns by a set of eight numerical parameters.
Reforming IMF ConditionalityFrom ‘streamlining’ to ‘major overhaul’

As it has for many years, International Monetary Fund conditionality is currently receiving much attention in the context of the global financial crisis. At the beginning of the 2000s the Fund introduced a policy of ‘streamlining’ intended to reduce the amount of conditionality and refocus it, with a view to increasing country ownership and improving programme implementation. This article uses the results of a report by the IMF’s Independent Evaluation Office into structural conditionality to assess the extent to which the initiative delivered on its promises. More significant seem to be the recent changes associated with the global crisis. The article discusses the evolution of conditionality, and assesses the current situation and the prospects for the future.
A quantitative approach to hepatic clearance prediction of metabolism by aldehyde oxidase using custom pooled hepatocytes

We describe the usability of human pooled hepatocytes for non-CYP metabolism evaluation and an in vivo–in vitro correlation analysis for aldehyde oxidase (AO) substrate compounds using pooled hepatocytes. By comparing intrinsic clearance values of 18 compounds primarily metabolized by AO, UDP-glucuronosyltransferase, carbonyl/aldo-keto reductase, flavin-containing monooxygenase, and monoamineoxidase in individual hepatocytes and pooled hepatocytes from the same individual donors, intrinsic clearance in the pooled hepatocytes was ±30% of the average clearance value in individuals for 15 of 18 compounds, suggesting that pooled hepatocytes maintained the average activity of the individual hepatocytes. Although the results of an in vivo–in vitro correlation analysis for AO substrate compounds showed a trend toward under-prediction, the underestimation ratios for all AO substrates were nevertheless comparable (7.2- to 14.9-fold), suggesting that hepatic clearance prediction for these compounds can be quantified using empirical scaling. These observations enabled us to obtain specific pooled hepatocytes that showed the expected non-CYP enzyme activities by pre-characterization and to quantify hepatic clearance prediction for AO compounds using an empirical scaling factor.
Environment-Dependent Distribution of the Sediment nifH-Harboring Microbiota in the Northern South China Sea

ABSTRACT The South China Sea (SCS), the largest marginal sea in the Western Pacific Ocean, is a huge oligotrophic water body with very limited influx of nitrogenous nutrients. This suggests that sediment microbial N2 fixation plays an important role in the production of bioavailable nitrogen. To test the molecular underpinning of this hypothesis, the diversity, abundance, biogeographical distribution, and community structure of the sediment diazotrophic microbiota were investigated at 12 sampling sites, including estuarine, coastal, offshore, deep-sea, and methane hydrate reservoirs or their prospective areas by targeting nifH and some other functional biomarker genes. Diverse and novel nifH sequences were obtained, significantly extending the evolutionary complexity of extant nifH genes. Statistical analyses indicate that sediment in situ temperature is the most significant environmental factor influencing the abundance, community structure, and spatial distribution of the sediment nifH-harboring microbial assemblages in the northern SCS (nSCS). The significantly positive correlation of the sediment pore water NH4 + concentration with the nifH gene abundance suggests that the nSCS sediment nifH-harboring microbiota is active in N2 fixation and NH4 + production. Several other environmental factors, including sediment pore water PO4 3− concentration, sediment organic carbon, nitrogen and phosphorus levels, etc., are also important in influencing the community structure, spatial distribution, or abundance of the nifH-harboring microbial assemblages. We also confirmed that the nifH genes encoded by archaeal diazotrophs in the ANME-2c subgroup occur exclusively in the deep-sea methane seep areas, providing for the possibility to develop ANME-2c nifH genes as a diagnostic tool for deep-sea methane hydrate reservoir discovery.
Unifying inconsistent evaluation metrics in recommender systems

Recommender systems are among the most popular tools used by online community these days. Traditionally, recommender techniques were evaluated using accuracy-based metrics such as precision; however, gradually the need for other qualities including more novel and diverse items emerged. Consequently, researchers started to evaluate their finding with different and often inconsistent metrics and made it nearly impossible to compare the existing approaches properly. It is clear that we need a more unified approach to assess the results of new techniques, and to the best of our knowledge, this problem has not been answered yet in previous studies. In this paper, we proposed a novel and extensible framework for evaluation of recommender systems using maximum bounds of possible measures in different datasets. Finally we provided the results of applying this framework on a set of different recommender algorithms.
Effect of different donor cells on human immunodeficiency virus type 1 replication and selection in vitro

We sought to determine the effects of different host cells on human immunodeficiency virus type 1 (HIV-1) infection in vitro. First, 17 primary viruses of various phenotypes were examined for replicative capacity in peripheral blood mononuclear cells (PBMC) from 10 healthy donors. While the range of infection was variable over a 40-fold range, it was substantially less than that previously reported (L. M. Williams and M. W. Cloyd, Virology 184:723-728, 1991). In particular, no donor cells demonstrated total resistance to HIV-1 infection. We next cocultured PBMC from an HIV-1-infected patient with stimulated PBMC from three healthy donors to determine the effect of host cells on selection for a particular HIV-1 quasispecies. By using DNA sequencing, it was found that the dominant quasispecies (AD30-15) after culture was nearly identical in the cells of different donors. Furthermore, after 6 months in vivo, the patient developed a dominant proviral population in PBMC that was most closely related to the quasispecies preferentially selected in vitro, although this quasispecies was only a minor fraction of the sequences present earlier in PBMC. In subsequent biological characterizations, it was found that AD30-15 grew much better in PBMC and macrophages than did other related quasispecies. Hence, we conclude that the primary mechanism of in vitro selection for a particular HIV-1 variant in this case is mediated by the phenotypic properties of the virus and is less dependent on host cell origin. The findings reported here have important practical implications for studies of HIV-1 replication in primary cells derived from healthy donors.
Refinement of the F-actin model against X-ray fiber diffraction data by the use of a directed mutation algorithm.

The F-actin model has been refined by a Directed Mutation Algorithm, a reiterative procedure which combines a Monte-Carlo method of selecting subdomains to be refined at each cycle with a non-linear least-squares routine to get the best fit for the particular selected domains. The G-actin crystal structure was used as a starting model. The experimental data were obtained by X-ray fiber diffraction patterns from oriented F-actin gels. After 250 cycles we were able to obtain an almost perfect fit of the calculated diffraction pattern to the experimental diffraction pattern as well as a reasonable stereochemistry including intermolecular interactions of the actin monomers with an r.m.s. shift in the C alpha-positions of 3.2 A from the crystal coordinates. The stereochemistry of the intersubunit packing was calculated by molecular dynamics using the program X-PLOR. In addition, the binding site of phalloidin, a cyclic heptapeptide from the mushroom Amanita phalloides, could be determined. Furthermore, we were able to determine differences in the structures of F-actin with and without phalloidin. The method proved itself robust and showed a high degree of convergence.
Synteny mapping of five human chromosome 7 genes on bovine chromosomes 4 and 21

Five genes on human chromosome 7 (HSA 7) were assigned to bovine chromosome 21 (BTA 21) and 4 (BTA 4) using a bovine-rodent somatic hybrid cell panel. These five genes were alpha-I subunit of adenylate cyclase-inhibiting G-protein (GNAI1), alpha/beta preprotachykinin (TAC1), reelin (RELN), c-AMP dependant protein kinase type II beta regulatory chain (PRKAR2B) and apolipoprotein A1 regulatory protein 1 (TFCOUP2). Four genes mapped to BTA 4 (GNAI1, TAC1, RELN, PRKAR2B) while one gene mapped to BTA 21 (TFCOUP2). This study confirms the synteny conservation between HSA 7 and BTA 4, finely maps the breakpoints of conserved synteny on HSA 7 and defines a new synteny conservation between HSA 7 and BTA 21.
Macroeconomic volatility effect on labour market performance

Macroeconomic volatility effect on labour market performance has been detected for OECD countries during the years of 1985-2011. Current research adds a number of improvements to the subject field. Labour market performance incorporates a large number of associative indicators rather than simple unemployment rate. Variety of performance indicators has been used in attempt to underpin the system mechanism. Advanced techniques are used for volatility estimation. Distinct volatility measures are used for exchange rate, inflation and interest rate series according to their stochastic properties. For long memory inflation series ARFIMA-GARCH models have been used, for interest rates that bare asymmetry due to Central Bank and market interventions QARCH, GJR-GARCH and PARCH models have been fitted. Exchange rate series have been modelled using ARIMA-GARCH and EGARCH. In estimation of volatility effect on labour market performance either random or fixed effects models have been used. Standard errors of the models have been tested and corrected for serial correlation, heteroskedasticity and cross-sectional dependence. For the robustness of the results panel time series methods have been used where possible due to its advantages for macroeconomics models (Eberhardt (2012)). Where use of these methods has been restricted by the nature of the models, Arellano-Bond (1991) and Bruno (2005) models have been fit. Hybrid (Allison (2009)) and Correlated Random effects models (Mundalak (1978) have been used where categorical variables have been included in the regression.
A comparison of methods for finding steady- state solution in power electronic circuits

This work concerns the fast steady-state determination of power electronic circuits. Switching converters operate in different modes. In each of these modes a converter is described as a linear time-invariant system (LTI). The steady state Is found with computer simulations performed with Newton-based methods for accelerated steady-state determination. Two methods are investigated: exact and approximated Jacobians. The implementation of zero-crossing detection improved convergence.
Evolution of Genotypic Resistance to Nucleoside Analogues in Patients Receiving Protease Inhibitor-Containing Regimens

The prevalence of genotypic resistance to nucleoside analogues (NA) was examined using a line probe assay (LiPA, Innogenetics, Spain) and a point mutation assay to test for codon 151 polymorphism in plasma from 34 individuals who had been exposed to NA for longer than 1 year. The testing was repeated in the same population after 6 months of being on a new potent protease inhibitor (PI)-containing antiretroviral combination. Only nine (47%) of the 19 patients initially carrying the codon 41 mutation restored zidovudine wild-type (WT) virus population. Similarly, eight (33%) out of 24 carrying the codon 215 mutation restored the wild-type variant. Two subjects carrying codon 74 didanosine mutation reverted to wild-type genotype, as well as two (18%) out of 11 harbouring the codon 184 lamivudine-resistant variant. To conclude, the extent to which drug recycling might be of benefit in subjects showing a restoration of genotypic sensitivity to former drugs needs to be explored.
NBER WORKING PAPER SERIES THE LABOR MARKET FOR TEACHERS UNDER DIFFERENT PAY SCHEMES

Compensation of most US public school teachers is rigid and solely based on seniority. This paper studies the labor market effects of a reform that gave school districts in Wisconsin full autonomy to redesign teacher pay schemes. Following the reform, some districts switched to flexible compensation and started paying high-quality teachers more. Teacher quality increased in these districts relative to those with seniority pay due to a change in workforce composition and an increase in effort. I estimate a structural model of this labor market to investigate the effects of counterfactual pay schemes on the composition of the teaching workforce. Barbara Biasi Yale School of Management 165 Whitney Avenue New Haven, CT 06520 and NBER barbara.biasi@yale.edu A online appendix is available at http://www.nber. org/data-appendix/w24813
The R Factor: Centering Race in the Mentoring of African American College Students

Mentoring provides personal support, academic assistance and career guidance to college students of color whose experiences have been documented to be very different from those of their White counterparts. Achievement inequity, problems of persistence, experiences of racism and student reports of feeling marginalized and misunderstood threaten the ability of students of color to succeed in college. While it may be assumed that race plays a central role in the mentoring relationships of students of color, this assumption may be misguided. The existence of formal mentoring programs and informal mentoring relationships that support students of color does not necessarily ensure that the confounded issue of race is appropriately embedded as a shaping force in the mentor/mentee association. This paper will deconstruct the assumption that approaches to the mentoring of students of color automatically consider race by applying Critical Race Theory as a theoretical framework to examine if and how race is present in the relationship between mentors and their African American student mentees at predominantly White institutions of higher education. Using phenomenological research design, this study brings race out of the rhetoric of higher education and places it in the center of examination to uncover student perceptions of race and how it operates within the mentoring relationship to help us better understand how we ensure high quality mentoring can be actively applied in our efforts to support the success of college students of color.