Miracle-dz/UniFAR-FTUs huggingface dataset:
The Role of Protein-Ligand Contacts in Allosteric Regulation of the Escherichia coli Catabolite Activator Protein*

Background: Protein allostery can be communicated purely through altered entropy. Results: Altered cAMP binding strength in CAP results in changes to entropy-driven allostery. Conclusion: The requirement to maintain allostery constrains evolution of the ligand-binding site in CAP. Significance: Entropy-driven processes can constrain amino acid covariation in evolution. Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distant site. Both experimental and theoretical evidence demonstrate that allostery can be communicated through altered slow relaxation protein dynamics without conformational change. The catabolite activator protein (CAP) of Escherichia coli is an exemplar for the analysis of such entropically driven allostery. Negative allostery in CAP occurs between identical cAMP binding sites. Changes to the cAMP-binding pocket can therefore impact the allosteric properties of CAP. Here we demonstrate, through a combination of coarse-grained modeling, isothermal calorimetry, and structural analysis, that decreasing the affinity of CAP for cAMP enhances negative cooperativity through an entropic penalty for ligand binding. The use of variant cAMP ligands indicates the data are not explained by structural heterogeneity between protein mutants. We observe computationally that altered interaction strength between CAP and cAMP variously modifies the change in allosteric cooperativity due to second site CAP mutations. As the degree of correlated motion between the cAMP-contacting site and a second site on CAP increases, there is a tendency for computed double mutations at these sites to drive CAP toward noncooperativity. Naturally occurring pairs of covarying residues in CAP do not display this tendency, suggesting a selection pressure to fine tune allostery on changes to the CAP ligand-binding pocket without a drive to a noncooperative state. In general, we hypothesize an evolutionary selection pressure to retain slow relaxation dynamics-induced allostery in proteins in which evolution of the ligand-binding site is occurring.
High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor*

Rev-erbα and Rev-erbβ are heme-binding nuclear receptors (NR) that repress the transcription of genes involved in regulating metabolism, inflammation, and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erbα recruits nuclear receptor corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases the affinity of the ligand-binding domain of Rev-erb NRs for NCoR1 peptides. One explanation for this discrepancy is that the ligand-binding domain and NCoR1 peptides used for in vitro studies cannot replicate the key features of the full-length proteins used in cellular studies. However, the combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erbβ (FLRev-erbβ) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo- and heme-replete FLRev-erbβ·DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erbβ·NCoR1 complex. The interaction between FLRev-erbβ and NCoR1 as well as Rev-erbβ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating the degradation of Rev-erbβ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10−6 s−1) of heme dissociation from Rev-erbβ rules out a prior proposal that Rev-erbβ acts as an intracellular heme sensor.
A multidisciplinary lifestyle intervention for childhood obesity : effects on body composition, exercise tolerance, quality of life and gut hormones

The general aim of the studies described in this thesis is the effect evaluation of a family-based multidisciplinary cognitive behavioral treatment on several domains related to childhood obesity compared to standard care. The main findings from these studies are a modest long-term reduction of both total and abdominal adiposity accompanied by improved physical fitness, while unchanged adiposity in the untreated controls led to decreased physical fitness and deteriorating insulin sensitivity. In addition, we found significantly impaired health related quality of life in the obese children compared to their normal weight peers. We showed that our multidisciplinary lifestyle treatment improved health related quality of life of the obese children after 1 year. We observed a significantly increased postprandial ghrelin response after the multidisciplinary treatment, but no effect on inflammatory markers, nor on gut hormones PYY and GLP-1. Finally, we propose an alternative for the definition of the metabolic syndrome in children, since the usefulness of its current dichotomous form is questionable. We show that a multivariate prediction model based on the individual components of the metabolic syndrome expressed as standard deviation scores (SDS) has a good predictive value regarding increased HOMA-IR SDS.
Impact of the type of catheter on the absorption of tylvalosin (acetylvaleryltylosin) administered orally to broiler chickens.

Pharmacokinetic and pharmacodynamic data are useful tointerpret the efﬁcacy and safety of a product. However,information on avian pharmacotherapy is scarce. Most of thepharmacokinetic studies on antimicrobials in chickens are basedon drugs applied orally using oral gavage. However, it is verydifﬁcult to ﬁnd a clear description of the type of catheter used forthe administration of the antimicrobials.Aivlosin (ECO Animal Health, London, UK), a water-solublepowder for the treatment of mycoplasmosis and other diseases inpoultry and swine production, contains the macrolide tylvalosin(acetylisovaleryltylosin) (Cerda´ et al., 2002, 2006a). During pilotstudies on the pharmacokinetics of tylvalosin in chickens, wefound a high variation in the absorption proﬁle not only betweenindividuals but also within individuals when used on separateoccasions. To investigate the cause of this variation, a study wasdesigned with the objective of analysing the impact of the qualityof the catheter used on the plasma kinetics of tylvalosin.A total of 12, 2-week-old chickens were used. Group A (sixchickens) received tylvalosin orally, through a ﬂexible 25-cm-length catheter (polyvinyl chloride), at a dosage of 20 mg⁄kgbodyweight (b.w.); group B (six chickens) received tylvalosinorally, through a rigid 25-cm-length catheter (stainless steelcannula), at a dosage of 20 mg⁄kg b.w. Blood samples (0.5 ml)were collected from the wing vein in heparinized tubes at thefollowing times: 0, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12and 24 h postadministration.Plasma was separated and frozen at )20 C until analysis. Allsamples were assayed on the week following collection. Tylvalosinplasma concentration was determined using a microbiologicalassay (Bennet et al., 1966) with Micrococcus luteus ATCC 9314as test micro-organism (Cerda´ et al., 2006b,c). The limit ofquantiﬁcation of the method was 0.05 lg ⁄ml. The method waslinear between 0.025 and 10 lg ⁄ml (r = 0.9974). Inter- andintra-assay coefﬁcients of variation were <10%. Individual birds tylvalosin concentration vs. time curves wereanalysed by nonlinear least square regression analysis using
Individual differences on the importance of virginity in Turkish society: An application on Turkish university students

Virginity is an important issue in Turkish society because of the position of virginity in both Islam and Turkish traditions and customs. As a result of the societal perspective of virginity, Turkish youth see virginity before marriage as an important judgmental value, especially for women. However, it is also observed that the ideas and views of Turkish youth are changing over time and with the influence of personal circumstances. The purpose of this study is to learn the ideas of Turkish youth about the importance of virginity and to depict individual differences by conducting a survey on students of the Faculty of Economics and Administrative Sciences of Eskisehir Osmangazi University. The participants were 664 university students attending different departments of the faculty in 2011-2012 academic year. A questionnaire including one dependent variable as the importance of virginity before marriage and sixteen independent variables was administered to students. QUEST analysis was applied to depict the research findings on a decision tree for more visual illustration. As a result of the analysis the most effective factor on the dependent variable was found students’ customs and usage. For the 65.38% of male students virginity is very important before marriage, for whom the customs and usage are important and who use alcohol and attend the third and fourth class, but for the 64.71% of the female students virginity is not important before marriage. The results of the analysis also showed that male and female individuals in Turkish society think in opposite ways about the importance of virginity before marriage.
Identification of Small Ankyrin 1 as a Novel Sarco(endo)plasmic Reticulum Ca2+-ATPase 1 (SERCA1) Regulatory Protein in Skeletal Muscle*

Background: Small ankyrin 1 (sAnk1) is required for stability of the network sarcoplasmic reticulum and shares transmembrane similarity with sarcolipin. Results: sAnk1-SERCA interactions and their effects on SERCA were demonstrated by co-immunoprecipitation, FRET, blot overlay, and Ca2+-ATPase assays. Conclusion: sAnk1 binds SERCA and reduces the affinity of SERCA for Ca2+. Significance: sAnk1 may play a role in maintaining Ca2+ homeostasis in skeletal muscle. Small ankyrin 1 (sAnk1) is a 17-kDa transmembrane (TM) protein that binds to the cytoskeletal protein, obscurin, and stabilizes the network sarcoplasmic reticulum in skeletal muscle. We report that sAnk1 shares homology in its TM amino acid sequence with sarcolipin, a small protein inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA). Here we investigate whether sAnk1 and SERCA1 interact. Our results indicate that sAnk1 interacts specifically with SERCA1 in sarcoplasmic reticulum vesicles isolated from rabbit skeletal muscle, and in COS7 cells transfected to express these proteins. This interaction was demonstrated by co-immunoprecipitation and an anisotropy-based FRET method. Binding was reduced ∼2-fold by the replacement of all of the TM amino acids of sAnk1 with leucines by mutagenesis. This suggests that, like sarcolipin, sAnk1 interacts with SERCA1 at least in part via its TM domain. Binding of the cytoplasmic domain of sAnk1 to SERCA1 was also detected in vitro. ATPase activity assays show that co-expression of sAnk1 with SERCA1 leads to a reduction of the apparent Ca2+ affinity of SERCA1 but that the effect of sAnk1 is less than that of sarcolipin. The sAnk1 TM mutant has no effect on SERCA1 activity. Our results suggest that sAnk1 interacts with SERCA1 through its TM and cytoplasmic domains to regulate SERCA1 activity and modulate sequestration of Ca2+ in the sarcoplasmic reticulum lumen. The identification of sAnk1 as a novel regulator of SERCA1 has significant implications for muscle physiology and the development of therapeutic approaches to treat heart failure and muscular dystrophies linked to Ca2+ misregulation.
Estrogenic Activities of Nitrophenols in Diesel Exhaust Particles1

Abstract We recently isolated 3-methyl-4-nitrophenol (4-nitro-m-cresol; PNMC) and 4-nitro-3-phenylphenol (PNMPP) from diesel exhaust particles (DEP) and identified them as vasodilators. Because these compounds are alkylphenolic derivatives that might mimic hormones, we evaluated their estrogenic activity by using recombinant yeast screens, myometrial contractility assays, and in vivo uterotrophic assays. Recombinant yeast screen assays showed that both PNMC and PNMPP possess estrogenic activity. Furthermore, ovariectomized 25-day-old immature female rats injected with PNMC and PNMPP subcutaneously for 2 days showed significant increases in uterine weight among those receiving 100 mg/kg PNMC and 0.1 and 1.0 mg/kg PNMPP. To clarify further the estrogenic activity of PNMC and PNMPP, rat uterine horns were monitored in organ bath chambers for myometrial contractility in response to oxytocin (OT). Significant differences occurred in the initial and maximum contractilities to OT at 0.25 and 25 mIU/ml in uterine horns obtained from animals treated with 100 mg/kg PNMC and in the maximum contractilities to OT at 0.025, 0.25, and 25 mIU/ml in those from rats treated with 0.1 mg/kg PNMPP. These results clearly demonstrated that PNMC and PNMPP in DEP have estrogenic activity both in vitro and in vivo and might therefore be considered as endocrine-disrupting chemicals.
Vector Error-Correction Models in a Consumer Packaged Goods Category Forecasting Decision Support System

A framework for developing marketing category management decision support systems (DSS) based upon the Bayesian Vector Autoregressive (BVAR) model is extended. Since the BVAR model is vulnerable to permanent and temporary shifts in purchasing patterns over time, a form that can correct for the shifts and still provide the other advantages of the BVAR is a Bayesian Vector Error-Correction Model (BVECM). We present the mechanics of extending the DSS to move from a BVAR model to the BVECM model for the category management problem. Several additional iterative steps are required in the DSS to allow the decision maker to arrive at the best forecast possible. The revised marketing DSS framework and model fitting procedures are described. Validation is conducted on a sample problem.
Purification of Active Respiratory Supercomplex from Bovine Heart Mitochondria Enables Functional Studies*

To understand the roles of mitochondrial respiratory chain supercomplexes, methods for consistently separating and preparing supercomplexes must be established. To this end, we solubilized supercomplexes from bovine heart mitochondria with digitonin and then replaced digitonin with amphipol (A8–35), an amphiphilic polymer. Afterward, supercomplexes were separated from other complexes by sucrose density gradient centrifugation. Twenty-six grams of bovine myocardium yielded 3.2 mg of amphipol-stabilized supercomplex. The purified supercomplexes were analyzed based on their absorption spectra as well as Q10 (ubiquinone with ten isoprene units) and lipid assays. The supercomplex sample did not contain cytochrome c but did contain complexes I, III, and IV at a ratio of 1:2:1, 6 molecules of Q10, and 623 atoms of phosphorus. When cytochrome c was added, the supercomplex exhibited KCN-sensitive NADH oxidation; thus, the purified supercomplex was active. Reduced complex IV absorbs at 444 nm, so we measured the resonance Raman spectrum of the reduced amphipol-solubilized supercomplex and the mixture of amphipol-solubilized complexes I1, III2, and IV1 using an excitation wavelength of 441.6 nm, allowing measurement precision comparable with that obtained for complex IV alone. Use of the purified active sample provides insights into the effects of supercomplex formation.
Portals in the Academic World: Are They Meeting Expectations?

This study investigates the status of portals in the academic world, including the adoption, implementation and evaluation of the portals. The results show that portals have received widespread attention in the academic world. Among those colleges who adopted the portals, half of them have horizontal portals and the majority of them have selected the Campus Pipeline software. The results also show that these portals mainly serve the needs of internal users by displaying campus wide information and to facilitate students in course related activities. The content of the portals in most schools is the responsibility of the IS/IT department. Integration and single logon are rated as the biggest challenges of implementing the portals. The results indicate that most schools have not formally evaluated their portals. The study also highlights the need for user participation and involvement in the implementation of campus portals, which has been ignored in most schools.
Synthetic Antibodies Inhibit Bcl-2-associated X Protein (BAX) through Blockade of the N-terminal Activation Site*

The BCL-2 protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Pro-apoptotic Bcl-2-associated X protein (BAX) is an executioner protein of the BCL-2 family that represents the gateway to mitochondrial apoptosis. Following cellular stresses that induce apoptosis, cytosolic BAX is activated and translocates to the mitochondria, where it inserts into the mitochondrial outer membrane to form a toxic pore. How the BAX activation pathway proceeds and how this may be inhibited is not yet completely understood. Here we describe synthetic antibody fragments (Fabs) as structural and biochemical probes to investigate the potential mechanisms of BAX regulation. These synthetic Fabs bind with high affinity to BAX and inhibit its activation by the BH3-only protein tBID (truncated Bcl2 interacting protein) in assays using liposomal membranes. Inhibition of BAX by a representative Fab, 3G11, prevented mitochondrial translocation of BAX and BAX-mediated cytochrome c release. Using NMR and hydrogen-deuterium exchange mass spectrometry, we showed that 3G11 forms a stoichiometric and stable complex without inducing a significant conformational change on monomeric and inactive BAX. We identified that the Fab-binding site on BAX involves residues of helices α1/α6 and the α1-α2 loop. Therefore, the inhibitory binding surface of 3G11 overlaps with the N-terminal activation site of BAX, suggesting a novel mechanism of BAX inhibition through direct binding to the BAX N-terminal activation site. The synthetic Fabs reported here reveal, as probes, novel mechanistic insights into BAX inhibition and provide a blueprint for developing inhibitors of BAX activation.
Sorbitol Can Fuel Mouse Sperm Motility and Protein Tyrosine Phosphorylation via Sorbitol Dehydrogenase1

Abstract Energy sources that can be metabolized to yield ATP are essential for normal sperm functions such as motility. Two major monosaccharides, sorbitol and fructose, are present in semen. Furthermore, sorbitol dehydrogenase (SORD) can convert sorbitol to fructose, which can then be metabolized via the glycolytic pathway in sperm to make ATP. Here we characterize Sord mRNA and SORD expression during mouse spermatogenesis and examine the ability of sorbitol to support epididymal sperm motility and tyrosine phosphorylation. Sord mRNA levels increased during the course of spermatogenic differentiation. SORD protein, however, was first detected at the condensing spermatid stage. By indirect immunofluorescence, SORD was present along the length of the flagella of caudal epididymal sperm. Furthermore, immunoelectron microscopy showed that SORD was associated with mitochondria and the plasma membranes of sperm. Sperm incubated with sorbitol maintained motility, indicating that sorbitol was utilized as an energy source. Sorbitol, as well as glucose and fructose, were not essential to induce hyperactive motility. Protein tyrosine phosphorylation increased in a similar manner when sorbitol was substituted for glucose in the incubation medium used for sperm capacitation. These results indicate that sorbitol can serve as an alternative energy source for sperm motility and protein tyrosine phosphorylation.
A Knowledge Component Analysis Model Based on Term Frequency and Correlation Analysis

Knowledge extraction, storage, management and reuse are the typical issues for an enterprise to maintain its competitiveness in the knowledge economy. Implicit knowledge of the domain experts is usually extracted and represented in the form of documents. The valuable knowledge lying in the documents should be explored and reconstructed by human beings through reading. Regarding the knowledge recognition issue, this paper proposes a model for document component analysis. In the proposed approach, two algorithms, namely frequency repository construction algorithm and document fragmentation algorithm, are developed. By construction of term frequency and correlation repositories, a comparison basis for document fragmentation is established. A web-based platform as well as a real case (i.e., analysis of intellectual property (IP) documents of automobile component designs) is provided to demonstrate the feasibility and performance of the proposed model. Concerning the importance of document contents and structure, the document fragmentation model can be applied in the enterprise knowledge management systems for efficient knowledge representation and acquisition.
Reflux and Renal Scarring

some of the more important growing aspects of the diagnosis and management of congenital heart disease, and contributors from America and Europe were chosen for their special experience in the subjects covered. These of necessity tend to be rather restricted, so that the book in no way represents a comprehensive account of modern paediatric cardiological practice as its title might suggest. As with all international symposia, the standard of contributions is variable. There is an excellent account of the new terminology in congenital heart disease and its relevance to the precise diagnosis of complex lesions, using the method of sequential chamber localisation which the editors themselves have done so much to promote during the last few years. Likewise, the sections on ventricular septal defect, Fallot's tetralogy, and atrioventricular canal defects, contain interesting material which is well presented. In particular, Rudolph's introductory review of ventricular septal defect in infancy is a small masterpiece of clarity and concise organisation of essential information. However, in other parts of the book, especially where the subject matter is more abstruse, both text and format tend to suffer from an unfortunate degree of repetitiveness. The free discussion that follows each major section, and which is generally of a high standard, enhances the interest and understanding of each subject. Because of its specialised and selective content, this book cannot be recommended as a work of reference for undergraduates