Miracle-dz/UniFAR-FTUs huggingface dataset:
Drug Binding in Human P-glycoprotein Causes Conformational Changes in Both Nucleotide-binding Domains*

The human multidrug resistance P-glycoprotein (P-gp, ABCB1) uses ATP to transport many structurally diverse compounds out of the cell. It is an ABC transporter with two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs). Recently, we showed that the “LSGGQ” motif in one NBD (531LSGGQ535 in NBD1;1176LSGGQ1180 in NBD2) is adjacent to the “Walker A” sequence (1070GSSGCGKS1077 in NBD2;427GNSGCGKS434 in NBD1) in the other NBD (Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2002)J. Biol. Chem. 277, 41303–41306). Drug substrates can stimulate or inhibit the ATPase activity of P-gp. Here, we report the effect of drug binding on cross-linking between the LSGGQ signature and Walker A sites (Cys431(NBD1)/C1176C(NBD2) and Cys1074(NBD2)/L531C(NBD1), respectively). Seven drug substrates (calcein-AM, demecolcine, cis(Z)-flupentixol, verapamil, cyclosporin A, Hoechst 33342, andtrans(E)-flupentixol) were tested for their effect on oxidative cross-linking. Substrates that stimulated the ATPase activity of P-gp (calcein-AM, demecolcine, cis(Z)-flupentixol, and verapamil) increased the rate of cross-linking between Cys431(NBD1-Walker A)/C1176C(NBD2-LSGGQ) and between Cys1074(NBD2-Walker A)/L531C(NBD1-LSGGQ) when compared with cross-linking in the absence of drug substrate. By contrast, substrates that inhibited ATPase activity (cyclosporin A, Hoechst 33342, andtrans(E)-flupentixol) decreased the rate of cross-linking. These results indicate that interaction between the LSGGQ motifs and Walker A sites must be essential for coupling drug binding to ATP hydrolysis. Drug binding in the transmembrane domains can induce long range conformational changes in the NBDs, such that compounds that stimulate or inhibit ATPase activity must decrease and increase, respectively, the distance between the Walker A and LSGGQ sequences.
Two-dimensional speckle tracking echocardiography: standardization efforts based on synthetic ultrasound data.

AIMS Speckle tracking echocardiography has already demonstrated its clinical potential. However, its use in routine practice is jeopardized by recent reports on high inter-vendor variability of the measurements. As such, the European Association of CardioVascular Imaging (EACVI) and the American Society of Echocardiography (ASE) set up a standardization task force, which was joined by all manufacturers of echocardiographic equipment as well as by companies offering software solutions only, with the ambition to tackle this problem by standardization and quality assurance (QA). METHODS AND RESULTS In this study, a first step towards QA of all commercially available tracking solutions based on computer-generated ultrasound images is presented. The accuracy of the products was acceptable with relative errors below 10% and intra-vendor reproducibility within 5%. CONCLUSION Whether these results can be extrapolated to the clinical setting is the topic of an ongoing study of the EACVI/ASE/Industry Task Force to standardize deformation imaging. This study was an important first step in the development of generally accepted tools for QA of speckle tracking echocardiography.
The Influence of Demographic Dissimilarity on Affective Reactions to Physical Activity Classes

The purpose of this study was to examine the effects of demographic dissimilarity from others on subsequent perceptions of differences and affective reactions toward physical activity classes. Students (N = 384) from a large southern university participated in the study. Structural equation modeling indicated that actual demographic dissimilarity from others in the class was positively related to perceptions of such differences. In addition, perceived demographic dissimilarity was positively associated with perceived deep-level differences (i.e., differences based on values, attitudes, and personality), which in turn negatively impacted affective reactions toward the class. Results are discussed in terms of theoretical contributions and implications for teaching physical activity classes.
Mega clinical trials which have shaped the RAS intervention clinical practice

Following extensive clinical research, drugs affecting the renin–angiotensin system have been used for the treatment of patients with congestive heart failure, myocardial infarction, hypertension, diabetic nephropathy, chronic renal failure and for reducing the risk of developing major cardiovascular (CV) events. This review examines all mega trials (those involving >1000 patients) and smaller pivotal trials involving angiotensin-converting enzyme inhibitors (ACE-Is; 25 mega trials) and angiotensin receptor blockers (ARBs; 27 mega trials) to provide perspective on the huge database of evidence that has accumulated on the use of these drugs. Our review demonstrates that ACE-Is and ARBs are generally as effective as conventional therapies in the treatment of hypertension, but offer additional cardioprotective benefits in patients with heart failure, and in those who have experienced myocardial infarction. Also, both ACE-Is and ARBs are capable of renal protection in addition to their blood-pressure-lowering effects. Although ACE-Is and ARBs provide major benefits to CV patients, doubts remain over the concept of blood-pressure-independent CV protection offered by both classes of drugs. ACE-Is and ARBs appear to be equally effective with respect to morbidity and mortality endpoints, but ARBs are better tolerated. Considering the available evidence, the combined use of an ACE-I and ARB should be avoided and full doses of either ACE-I or ARB should be aimed for as evidence suggests they provide a greater prognostic benefit.
Recognition of merged characters based on forepart prediction, necessity-sufficiency matching, and character-adaptive masking

Merged characters are the major cause of recognition errors. We classify the merging relationship between two involved characters into three types: "linear", " nonlinear", and "overlapped". Most segmentation methods handle the first type well, however, their capabilities of handling the other two types are limited. The weakness of handling the nonlinear and overlapped types results from character segmentation by linear, usually vertical, cuts assumed in these methods. This paper proposes a novel merged character segmentation and recognition method based on forepart prediction, necessity-sufficiency matching and character-adaptive masking. This method utilizes the information obtained from the forepart of merged characters to predict candidates for the leftmost character, and then applies character-adaptive masking and character recognition to verifying the prediction. Therefore, the arbitrary-shaped cutting path will follow the right shape of the leftmost character so as to preserve the shape of the next character. This method handles the first two types well and greatly improves the segmentation accuracy of the overlapped type. The experimental results and the performance comparisons with other methods demonstrate the effectiveness of the proposed method.
English second language learners: using music to enhance the listening abilities of grade ones

Music is a form of language and uses tones and rhythm as its media of universal language. Language development and music development have many similarities. Both are communicative modes, aurally and orally transmitted, containing phonetic, syntactic, and semantic components, develop early in life and are socially interactive media. The researcher has noted the important role that music plays in the teaching of English as a second language. To be able to learn, understand and experience music and language, the learner should have well-developed listening skills. The aim of this research is to investigate the use of music and movement to develop the listening skills of the ESL learner. To provide activities to develop listening and concentration through music and movement, the researcher aims to prove that music and movement should be used to develop ESL learners' language.
The Cosmic Reionization History as Revealed by the Cosmic Microwave Background Doppler-21 cm Correlation

We show that the epoch(s) of reionization when the average ionization fraction of the universe is about half can be determined by correlating CMB temperature maps with 21 cm line maps at degree scales (l ~ 100). During reionization peculiar motion of free electrons induces the Doppler anisotropy of the CMB, while density fluctuations of neutral hydrogen induce the 21 cm line anisotropy. In our simplified model of inhomogeneous reionization, a positive correlation arises as the universe reionizes whereas a negative correlation arises as the universe recombines; thus, the sign of the correlation provides information on the reionization history that cannot be obtained by present means. The signal comes mainly from large scales (k ~ 10-2 Mpc-1) where linear perturbation theory is still valid and complexity due to patchy reionization is averaged out. Since the Doppler signal comes from ionized regions and the 21 cm comes from neutral ones, the correlation has a well-defined peak(s) in redshift when the average ionization fraction of the universe is about half. Furthermore, the cross-correlation is much less sensitive to systematic errors, especially foreground emission, than the autocorrelation of 21 cm lines; this is analogous to the temperature-polarization correlation of the CMB being more immune to systematic errors than the polarization-polarization. Therefore, we argue that the Doppler-21 cm correlation provides a robust measurement of the 21 cm anisotropy, which can also be used as a diagnostic tool for detected signals in the 21 cm data—detection of the cross-correlation provides the strongest confirmation that the detected signal is of cosmological origin. We show that the Square Kilometer Array can easily measure the predicted correlation signal for 1 yr of survey observation.
PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing

New HIV therapies are urgently needed to address the growing problem of drug resistance. In this article, we characterize the anti-HIV drug candidate 3-O-(3′,3′-dimethylsuccinyl) betulinic acid (PA-457). We show that PA-457 potently inhibits replication of both WT and drug-resistant HIV-1 isolates and demonstrate that the compound acts by disrupting a late step in Gag processing involving conversion of the capsid precursor (p25) to mature capsid protein (p24). We find that virions from PA-457-treated cultures are noninfectious and exhibit an aberrant particle morphology characterized by a spherical, acentric core and a crescent-shaped, electron-dense shell lying just inside the viral membrane. To identify the determinants of compound activity we selected for PA-457-resistant virus in vitro. Consistent with the effect on Gag processing, we found that mutations conferring resistance to PA-457 map to the p25 to p24 cleavage site. PA-457 represents a unique class of anti-HIV compounds termed maturation inhibitors that exploit a previously unidentified viral target, providing additional opportunities for HIV drug discovery.
Optimising Fault Detection and Exclusion in positioning

Reliability and integrity has become increasingly important in ubiquitous positioning systems, and particularly in critical applications. To implement reliability and integrity measures, Fault Detection and Exclusion (FDE) procedures should be used. However, the current FDE procedures in the chi-square test and the outlier test are suboptimal in terms of continuity and availability. This is due to the assumption that the bias always corresponds with the measurement that has the largest Protection Level (PL), and in the setting of the continuity probability to a predefined value rather than being maximised.
Cell migration by a FRS2‐adaptor dependent membrane relocation of ret receptors

During development neural progenitor cells migrate with extraordinary precision to inhabit tissues and organs far from their initial position. Little is known about the cellular basis for directional guidance by tyrosine kinase receptors (RTKs). RET is a RTK with important functions in guiding the migration of neuronal cells, and RET dysregulation leads to clinical disease such as agangliosis of the colon. We show here that RET migration in neuroepitheliomal and non‐neuronal cells is elicited by the activation of specific signaling pathways initiated by the competitive recruitment of the FRS2 adaptor molecule to tyrosine 1062 (Y1062) in RET. FRS2 selectively recruited RET to focal complexes and led to activation of SRC family kinases and focal adhesion kinase (FAK). Activation of SRC depended on its direct interaction with RET at a different intracellular tyrosine (Y981) and activation of molecular signaling from these two separate sites in concert regulated migration. Our data suggest that an important function for FRS2 is to concentrate RET in membrane foci, leading to an engagement of specific signaling complexes localized in these membrane domains. J. Cell. Biochem. 104: 879–894, 2008. © 2008 Wiley‐Liss, Inc.
Functional Roles of Nonconserved Structural Segments in CFTR's NH2-terminal Nucleotide Binding Domain

The cystic fibrosis transmembrane conductance regulator (CFTR), encoded by the gene mutated in cystic fibrosis patients, belongs to the family of ATP-binding cassette (ABC) proteins, but, unlike other members, functions as a chloride channel. CFTR is activated by protein kinase A (PKA)-mediated phosphorylation of multiple sites in its regulatory domain, and gated by binding and hydrolysis of ATP at its two nucleotide binding domains (NBD1, NBD2). The recent crystal structure of NBD1 from mouse CFTR (Lewis, H.A., S.G. Buchanan, S.K. Burley, K. Conners, M. Dickey, M. Dorwart, R. Fowler, X. Gao, W.B. Guggino, W.A. Hendrickson, et al. 2004. EMBO J. 23:282–293) identified two regions absent from structures of all other NBDs determined so far, a “regulatory insertion” (residues 404–435) and a “regulatory extension” (residues 639–670), both positioned to impede formation of the putative NBD1–NBD2 dimer anticipated to occur during channel gating; as both segments appeared highly mobile and both contained consensus PKA sites (serine 422, and serines 660 and 670, respectively), it was suggested that their phosphorylation-linked conformational changes might underlie CFTR channel regulation. To test that suggestion, we coexpressed in Xenopus oocytes CFTR residues 1–414 with residues 433–1480, or residues 1–633 with 668–1480, to yield split CFTR channels (called 414+433 and 633+668) that lack most of the insertion, or extension, respectively. In excised patches, regulation of the resulting CFTR channels by PKA and by ATP was largely normal. Both 414+433 channels and 633+668 channels, as well as 633(S422A)+668 channels (lacking both the extension and the sole PKA consensus site in the insertion), were all shut during exposure to MgATP before addition of PKA, but activated like wild type (WT) upon phosphorylation; this indicates that inhibitory regulation of nonphosphorylated WT channels depends upon neither segment. Detailed kinetic analysis of 414+433 channels revealed intact ATP dependence of single-channel gating kinetics, but slightly shortened open bursts and faster closing from the locked-open state (elicited by ATP plus pyrophosphate or ATP plus AMPPNP). In contrast, 633+668 channel function was indistinguishable from WT at both macroscopic and microscopic levels. We conclude that neither nonconserved segment is an essential element of PKA- or nucleotide-dependent regulation.
Successive dynamic programming and subsequent spline optimization for smooth time optimal robot path tracking

Abstract. The time optimal path tracking for industrial robots regards the problem of generating trajectories that follow predefined end-effector (EE) paths in shortest time possible taking into account kinematic and dynamic constraints. The complicated tasks used in industrial applications lead to very long EE paths. At the same time smooth trajectories are mandatory in order to increase the service life. The consideration of jerk and torque rate restrictions, necessary to achieve smooth trajectories, causes enormous numerical effort, and increases computation times. This is in particular due to the high number of optimization variables required for long geometric paths. In this paper we propose an approach where the path is split into segments. For each individual segment a smooth time optimal trajectory is determined and represented by a spline. The overall trajectory is then found by assembling these splines to the solution for the whole path. Further we will show that by using splines, the jerks are automatically bounded so that the jerk constraints do not have to be imposed in the optimization, which reduces the computational complexity. We present experimental results for a six-axis industrial robot. The proposed approach provides smooth time optimal trajectories for arbitrary long geometric paths in an efficient way.
Brain surface segmentation of Magnetic Resonance images of the fetus

In this work we present a method for the image analysis of Magnetic Resonance Imaging (MRI) of fetuses. Our goal is to segment the brain surface from multiple volumes (axial, coronal and sagittal acquisitions) of a fetus. To this end we propose a two-step approach: first, a Finite Gaussian Mixture Model (FGMM) will segment the image into 3 classes: brain, non-brain and mixture voxels. Second, a Markov Random Field scheme will be applied to re-distribute mixture voxels into either brain or non-brain tissue. Our main contributions are an adapted energy computation and an extended neighborhood from multiple volumes in the MRF step. Preliminary results on four fetuses of different gestational ages will be shown.
Flavonoid-rich beverage effects on lipid profile and blood pressure in diabetic patients.

AIM To compare freeze-dried strawberry (FDS) beverage and strawberry-flavored drink effects on lipid profile and blood pressure in type 2 diabetic (T2D) patients. METHODS In a randomized, double-blind, controlled trial, 36 subjects with T2D (23 females; mean ± SE age: 51.57 ± 10 years) were randomly divided into two groups. Participants consumed two cups of either pure FDS beverage (each cup containing 25 g freeze-dried strawberry powder equivalent to one serving of fresh strawberries; intervention group) or an iso-caloric drink with strawberry flavoring (similar to the FDS drink in fiber content and color; placebo group) daily for 6 wk. Anthropometric measurements, 3 d, 24 h dietary recall, and fasting blood samples were collected at baseline and at weeks 6 intervention. After lying down and relaxing for approximately 10 min, each participant's blood pressure was recorded in triplicate with 5 min intervals; recordings were made at baseline and the trial end-point. Each participant's lipid profile was assessed before and after intervention. RESULTS Assessment at the weeks 6 intervention showed a significant reduction from baseline in total cholesterol levels and total cholesterol to high-density lipoprotein cholesterol (HDL-C) ratio in the intervention group (179.01 ± 31.86 to 165.9 ± 32.4 mg/L; P = 0.00 and 3.9 ± 0.88 to 3.6 ± 0.082 mg/L; P = 0.00 respectively), but the change was not significantly different between the two groups (P = 0.07, P = 0.29 respectively). Systolic blood pressure levels were significantly reduced from baseline in both the FDS and placebo drink groups (129.95 ± 14.9 to 114.3 ± 27.5 mmHg; P = 0.02 and 127.6 ± 15.6 to 122.9 ± 14.47 mmHg; P = 0.00 respectively), but the reduction was not significantly different between the two groups. Diastolic blood pressure was significantly reduced post-intervention in the FDS drink group compared to placebo group (78.7 ± 7.2 vs 84.4 ± 5.8; P = 0.01), the reduction was also significant within the FDS drink group (84.2 ± 8.03 to 78.7 ± 7.2; P = 0.00). Triglycerides, HDL-C concentrations and anthropometric indices showed no significant differences between or within groups. CONCLUSION Short-term FDS supplementation improved selected cardiovascular risk factors in subjects with T2D. Long-term effects on other metabolic biomarkers need to be investigated in future trials.
Lethality patterns and morphology of selected lethal and semi-lethal mutations in the zeste-white region of Drosophila melanogaster.

Aspects of the developmental genetics of lethal and semi-lethal mutants representing 13 complementation groups (cistrons) in the 3A-3C region of the X chromosome of Drosophila melanogaster are given. Each of these cistrons is associated with a particular chromomere in the salivary gland chromosome. Mutants within each cistron have similar lethality patterns and morphological attributes, and the characteristics of a given cistron are distinct with respect to other cistrons. These results provide additional evidence that only one function is associated with each chromomere. -The results of the lethality pattern analysis are also compared with previous studies of lethal mutants of Drosophila.
PNEUMATICALLY ACTUATED EXOSKELETON FOR GAIT REHABILITATION

This paper describe the mechanical and control syst em design of a 10 DOF (Degrees Of Freedom) lower limbs exoskeleton for gait rehabilitation of patients with gait dysfu nction. The system has 4 double-acting rod pneumati c actuators (two for each leg), that controls the hip and knee joints. M otion of each cylinder’s piston is controlled by tw o pressure proportional valves, connected to both cylinder chambers. The pn eumatic actuators are controlled by proportional-pr essure valves. The control strategy has been specifically designed in order to ensure a proper position control guiding p atient’s legs along a fixed reference gait pattern. For this purposes Fuz zy controller with additional force compensator was developed. A numerical solution of the inverse kinematics proble m based on video image analysis has been used. The controller was successively implemented and tested on embedded real-time PC104 system. Laboratory experiments without patient are carried out and the results are reported and discus sed.
An Effective Approach for Iris Recognition Using Phase-Based Image Matching

This paper presents an efficient algorithm for iris recognition using phase-based image matching - an image matching technique using phase components in 2D discrete Fourier transforms (DFTs) of given images. Experimental evaluation using the CASIA iris image databases (versions 1.0 and 2.0) and Iris challenge evaluation (ICE) 2005 database clearly demonstrates that the use of phase components of iris images makes it possible to achieve highly accurate iris recognition with a simple matching algorithm. This paper also discusses the major implementation issues of our algorithm. In order to reduce the size of iris data and to prevent the visibility of iris images, we introduce the idea of 2D Fourier phase code (FPC) for representing iris information. The 2D FPC is particularly useful for implementing compact iris recognition devices using state-of-the-art digital signal processing (DSP) technology.