Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanism-Based Inactivation of Human Cytochrome P4502C8 by Drugs in Vitro

Studies were conducted to evaluate the potential mechanism-based inactivation of recombinant and human liver microsomal CYP2C8 by clinically used drugs. Several tricyclic antidepressants, calcium channel blockers, monoamine oxidase inhibitors, and various other known CYP3A4 inhibitors exhibited greater inhibition of CYP2C8 (paclitaxel 6α-hydroxylation) following preincubation, consistent with mechanism-based inactivation. Inactivation of recombinant CYP2C8 by phenelzine, amiodarone, verapamil, nortriptyline, fluoxetine, and isoniazid was of the pseudo-first order type and was characterized by respective inactivation kinetic constants (KI and kinact) of 1.2 μM and 0.243 min–1, 1.5 μM and 0.079 min–1, 17.5 μM and 0.065 min–1, 49.9 μM and 0.036 min–1, 294 μM and 0.083 min–1, and 374 μM and 0.042 min–1. Spectral scanning of recombinant CYP2C8 demonstrated the formation of metabolite-intermediate complexes with verapamil, nortriptyline, fluoxetine, and isoniazid, but not amiodarone. In contrast, inactivation by phenelzine resulted from heme destruction by free radicals. Studies with human liver microsomes (HLMs) revealed that nortriptyline, verapamil, and fluoxetine were not mechanism-based inactivators (MBIs) of CYP2C8. Simultaneous inactivation of CYP2C8 and CYP3A4 (paclitaxel 3′-phenyl-hydroxylation) was observed using amiodarone, isoniazid, and phenelzine with the efficiency of inactivation greater for the CYP3A4 pathway. With the exception of phenelzine, glutathione and superoxide dismutase failed to protect CYP2C8 (recombinant and HLMs) or CYP3A4 from inactivation by MBIs. However, the alternate CYP2C8 substrate, torsemide, prevented CYP2C8 inactivation in all cases. These data are consistent with mechanism-based inactivation of CYP2C8 by a range of commonly prescribed drugs, several of which have been implicated in clinically important drug-drug interactions.
Dysembryoplastic Neuroepithelial Tumor in the Left Lateral Ventricle

Extracortical location of dysembryoplastic neuroepithelial tumor (DNT) is rare. We present a case of DNT localized in the left lateral ventricle of a 21-year-old female patient. Magnetic resonance imaging of the brain showed a round mass lesion in the floor of the anterior horn of the left lateral ventricle. The lesion was hypointense on T (1)-weighted images and slightly hyperintense on T (2)-weighted images without contrast enhancement. Total removal of the yellowish-white colored soft tumor was performed through a transcallosal approach. Histologically, the tumor was of simple type of DNT that was composed of small oligodendrogliocytes clustered tightly about perivascular spaces with neurons floating in mucoid pools showing an eosinophilic fibrillary matrix in the background. The recognition of DNT with an unusual location in lateral ventricle has therapeutic and prognostic significance since DNT is curable by surgical excision and radiation therapy is of no obvious benefit.
Prevalence and correlates of the perpetration of cyberbullying among in-school adolescents in Oyo State, Nigeria

Abstract Objective: Cyberharassment/cyberbullying is a global problem that has been inadequately investigated in developing countries. In this paper, we present findings on the prevalence and predictors of perpetration of cyberbullying among in-school adolescents in Oyo state, Nigeria. Methods: A total of 653 students were selected via multi-stage sampling. Information on history of perpetrating harassment via an electronic medium in the 3-month period preceding the survey was obtained. Results: Respondents’ mean age was 14.2±2.2 years and 51.3% were females. All respondents had personal mobile phones and about half had Internet access. About 40% accessed the Internet every day while about 48% accessed it at least once to several times a week and <5% accessed it about once every 2 weeks. One hundred and fifty-six (23.9%) had harassed someone electronically, 260 (39.8%) had been victimized, and 137 (21.0%) were both victims and perpetrators. Common modes of harassment were via phone calls 99 (63.5%), chat rooms 70 (44.9%), and text messages 60 (38.5%). Students who had been victims of cyberbullying (OR=21.76, 95% CI=12.64–37.47) and those with daily Internet access (OR=2.32, 95% CI=1.28–4.19) had significantly higher Oods of being perpetrators. Conclusion: About a quarter of students were perpetrators of cyberbullying, and the correlates of perpetration were history of cyber victimization and daily Internet access. Intervention programs must be instituted for victims as well as frequent users of the Internet to curb the problem in the study area.
c-Abl-mediated Phosphorylation of WAVE3 Is Required for Lamellipodia Formation and Cell Migration*

The activity of the Wiskott-Aldrich syndrome-related WAVE3 protein is critical for the regulation of the Arp2/3-dependent cytoskeleton organization downstream of Rac-GTPase. The Ableson (Abl) non-receptor tyrosine kinase is also involved in the remolding of actin cytoskeleton in response to extracellular stimuli. Here we show that platelet-derived growth factor stimulation of cultured cells results in WAVE3-Abl interaction and localization to the cell periphery. WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. We have also shown that Abl targets and phosphorylates four tyrosine residues in WAVE3 and that the Abl-dependent phosphorylation of WAVE3 is critical for the stimulation of lamellipodia formation and cell migration. Our results show that the activation of WAVE3 to promote actin remodeling is enhanced by the c-Abl-mediated tyrosine phosphorylation of WAVE3.
The PY Motif of ENaC, Mutated in Liddle Syndrome, Regulates Channel Internalization, Sorting and Mobilization from Subapical Pool

The epithelial‐Na+‐channel (αβγENaC) regulates kidney salt‐transport and blood pressure. Each ENaC subunit contains a PY motif (PPxY) and its mutation in β/γENaC causes Liddle syndrome, a hereditary hypertension. These (extended) PY motifs (PP616xY618xxL621) serve as binding sites for the ubiquitin ligase Nedd4‐2, which decreases cell‐surface expression of ENaC by unknown route(s). Using polarized kidney epithelia [Madin‐Darby canine kidney I (MDCK‐I)] cells stably expressing extracellularly myc‐tagged wild type (WT) or PY‐motif mutants of βENaC (P616A, Y618A or L621A, with WT‐αγENaC), and live‐imaging plus enzyme‐linked immunosorbent assay (ELISA)‐type assays to analyze routes/rates of ENaC internalization/recycling, we show here that cell‐surface half‐life of all PY mutants was fourfold longer than WT‐ENaC (∼120 versus 30 minutes), reflecting primarily reduced channel internalization but also attenuated replenishment of cell‐surface ENaC from a large subapical pool. The Y618A mutant revealed more severe internalization and replenishment defects than the other PY mutants. Internalized WT‐ENaC was detected in sorting/recycling and late endosomes/lysosomes, while the Y618A mutant accumulated in the former. Nedd4‐2 ubiquitinated ENaC at the apical membrane causing channel internalization and degradation. Cyclic AMP (cAMP) accelerated mobilization of subapical ENaC to the cell surface and long‐term ENaC recycling, but only mobilization, not recycling, was inhibited in the PY mutants. These results suggest that the ENaC PY motifs (and Nedd4‐2) primarily regulate channel internalization but also affect cAMP‐dependent replenishment, providing important insight into the Liddle syndrome defects.
Structural Intermediates in the Putative Pathway from the Cellular Prion Protein to the Pathogenic Form

Abstract The conversion of the αhelical, protease sensitive and noninfectious form of the prion protein (PrP) into an insoluble, protease resistant, predominantly βsheeted and infectious form (PrP) is the fundamental event in prion formation. In the present work, two soluble and stable intermediate structural states are newly identified for recombinant Syrian hamster PrP(90 231) (recPrP), a dimeric αhelical state and a tetra or oligomeric, βsheet rich state. In 0.2% SDS at room temperature, recPrP is soluble and exhibits αhelical and random coil secondary structure as determined by circular dichroism. Reduction of the SDS concentration to 0.06% leads first to a small increase in αhelical content, whereas further dilution to 0.02% results in the aquisition of βsheet structure. The reversible transition curve is sigmoidal within a narrow range of SDS concentrations (0.04 to 0.02%). Size exclusion chromatography and chemical crosslinking revealed that the αhelical form is dimeric, while the βsheet rich form is tetra or oligomeric. Both the αhelical and βsheet rich intermediates are soluble and stable. Thus, they should be accessible to further structural and mechanistic studies. At 0.01% SDS, the oligomeric intermediates aggregated into large, insoluble structures as observed by fluorescence correlation spectroscopy. Our results are discussed with respect to the mechanism of PrP formation and the propagation of prions.
Identification of extracellularly phosphorylated membrane proteins

Ecto‐protein kinases phosphorylate extracellular membrane proteins and exhibit similarities to casein kinases and protein kinases A and C. However, the identification of their protein substrates still remains a challenge because a clear separation from intracellular phosphoproteins is difficult. Here, we describe a straightforward method for the identification of extracellularly phosphorylated membrane proteins in human umbilical vein endothelial cells (HUVECs) and K562 cells which used the protease bromelain to selectively remove ectoproteins from intact cells and combined this with the subsequent analysis using IMAC and LC‐MS/MS. A “false‐positive” strategy in which cells without protease treatment served as controls was applied. Using this approach we identified novel phosphorylation sites on five ectophosphoproteins (NOTCH1, otopetrin 1, regulator of G‐protein signalling 13 (RGS13), protein tyrosine phosphatase receptor type D isoform 3 (PTPRD), usherin isoform B (USH2A)). Use of bromelain appears to be a reliable technique for the further identification of phosphorylated surface‐exposed peptides when extracellular adenosine‐5'‐triphosphate is elevated during purinergic signalling.
An Efficient Refining Image Annotation Technique by Combining Probabilistic Latent Semantic Analysis and Random Walk Model

In this paper, we present a new method for refining image annotation based on a combination of probabilistic latent semantic analysis (PLSA) and random walk (RW). We first construct a PLSA model with asymmetric modalities to estimate the posterior probabilities of each annotation keywords for one image, and then a label similarity graph is constructed by a weighted linear combination of label similarity and visual similarity. Followed by a random walk process over a label graph is employed to further mine the correlation of the keywords so as to capture the refining annotation, which is very important for semantic-based image retrieval. The novelty of our method mainly lies in two aspects: exploiting PLSA to accomplish the initial semantic annotation task and implementing random walk process over the constructed label similarity graph to refine the candidate annotations generated by the PLSA. Compared with several state-of-the-art approaches on Corel5k and Mirflickr25k datasets, the experimental results s.
Antimicrobial properties of plant essential oils and essences against five important food‐borne pathogens

The antimicrobial properties of 21 plant essential oils and two essences were investigated against five important food‐borne pathogens, Campylobacter jejuni, Salmonella enteritidis, Escherichia coli, Staphylococcus aureus and Listeria monocytogenes. The oils of bay, cinnamon, clove and thyme were the most inhibitory, each having a bacteriostatic concentration of 0·075% or less against all five pathogens. In general, Gram‐positive bacteria were more sensitive to inhibition by plant essential oils than the Gram‐negative bacteria. Campylobacter jejuni was the most resistant of the bacteria investigated to plant essential oils, with only the oils of bay and thyme having a bacteriocidal concentration of less than 1%. At 35 °C, L. monocytogenes was extremely sensitive to the oil of nutmeg. A concentration of less than 0·01% was bacteriostatic and 0·05% was bacteriocidal, but when the temperature was reduced to 4 °C, the bacteriostatic concentration was increased to 0·5% and the bacteriocidal concentration to greater than 1%.
Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f

Mutations in human KCNE2, which encodes the MiRP1 potassium channel ancillary subunit, associate with long QT syndrome (LQTS), a defect in ventricular repolarization. The precise cardiac role of MiRP1 remains controversial, in part, because it has marked functional promiscuity in vitro. Here, we disrupted the murine kcne2 gene to define the role of MiRP1 in murine ventricles. kcne2 disruption prolonged ventricular action potential duration (APD), suggestive of reduced repolarization capacity. Accordingly, kcne2 (−/−) ventricles exhibited a 50% reduction in IK,slow1, generated by Kv1.5—a previously unknown partner for MiRP1. Ito,f, generated by Kv4 α subunits, was also diminished, by ~25%. Ventricular MiRP1 protein coimmunoprecipitated with native Kv1.5 and Kv4.2 but not Kv1.4 or Kv4.3. Unexpectedly, kcne2 (−/−) ventricular membrane fractions exhibited 50% less mature Kv1.5 protein than wild type, and disruption of Kv1.5 trafficking to the intercalated discs. Consistent with the reduction in ventricular K+ currents and prolonged ventricular APD, kcne2 deletion lengthened the QTc under sevoflurane anesthesia. Thus, targeted disruption of kcne2 has revealed a novel cardiac partner for MiRP1, a novel role for MiRPs in α subunit targeting in vivo, and a role for MiRP1 in murine ventricular repolarization with parallels to that proposed for the human heart. —Roepke, T. K. , Kontogeorgis, A. , Ovanez, C. , Xu, X. , Young, J. B. , Purtell, K. , Goldstein, P. A. , Christini, D. J., Peters, N. S. , Akar, F. G. , Gutstein, D. E. , Lerner, D. J., Abbott, G. W. Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f. FASEB J. 22, 3648–3660 (2008)
Positive regulation by small RNAs and the role of Hfq

Bacterial small noncoding RNAs carry out both positive and negative regulation of gene expression by pairing with mRNAs; in Escherichia coli, this regulation often requires the RNA chaperone Hfq. Three small regulatory RNAs (sRNAs), DsrA, RprA, and ArcZ, positively regulate translation of the sigma factor RpoS, each pairing with the 5′ leader to open up an inhibitory hairpin. In vitro, rpoS interaction with sRNAs depends upon an (AAN)4 Hfq-binding site upstream of the pairing region. Here we show that both Hfq and this Hfq binding site are required for RprA or ArcZ to act in vivo and to form a stable complex with rpoS mRNA in vitro; both were partially dispensable for DsrA at 37 °C. ArcZ sRNA is processed from 121 nt to a stable 56 nt species that contains the pairing region; only the 56 nt ArcZ makes a strong Hfq-dependent complex with rpoS. For each of these sRNAs, the stability of the sRNA•mRNA complexes, rather than their rate of formation, best predicted in vivo activity. These studies demonstrate that binding of Hfq to the rpoS mRNA is critical for sRNA regulation under normal conditions, but if the stability of the sRNA•mRNA complex is sufficiently high, the requirement for Hfq can be bypassed.
Personality, uses of music, and music preference: The influence of openness to experience and extraversion

The purpose of this study was to ascertain whether uses of music partially mediate the link between personality and music preference. Undergraduate students (N = 122) completed the following scales: The Brief Big Five Inventory, The Uses of Music Inventory, The Short Test of Music Preference, The Life Orientation Test Revised, The Beck Depression Inventory, and the Perceived Stress Scale. Openness to experience positively predicted preferences for reflective-complex (RC; e.g., jazz/blues) and intense-rebellious (IR; e.g., rock/metal) music and was inversely related to upbeat-conventional (UC; e.g., country/pop) music, whereas extraversion was positively related to preferences for energetic-rhythmic (ER; e.g., rap/soul) and UC genres. A link between trait optimism and ER music preference was fully mediated by the more prominent extraversion trait. The relationship between openness to experience and RC music preference was partially mediated by cognitive uses of music, with a marginally significant analysis indicating partial mediation of emotional uses of music for openness to experience and IR music preference. Trait neuroticism, perceived stress, and depression scores all correlated positively with emotional uses of music. The current findings support studying personality contextually alongside uses of music when investigating music preference and shed light on how negative affect may inform emotional uses of music.
An Apoplastic H-Type Thioredoxin Is Involved in the Stress Response through Regulation of the Apoplastic Reactive Oxygen Species in Rice1[C][W][OA]

Thioredoxins (Trxs) are a multigenic family of proteins in plants that play a critical role in redox balance regulation through thiol-disulfide exchange reactions. There are 10 members of the h-type Trxs in rice (Oryza sativa), and none of them has been clearly characterized. Here, we demonstrate that OsTRXh1, a subgroup I h-type Trx in rice, possesses reduction activity in vitro and complements the hydrogen peroxide sensitivity of Trx-deficient yeast mutants. OsTRXh1 is ubiquitously expressed in rice, and its expression is induced by salt and abscisic acid treatments. Intriguingly, OsTRXh1 is secreted into the extracellular space, and salt stress in the apoplast of rice induces its expression at the protein level. The knockdown of OsTRXh1 results in dwarf plants with fewer tillers, whereas the overexpression of OsTRXh1 leads to a salt-sensitive phenotype in rice. In addition, both the knockdown and overexpression of OsTRXh1 decrease abscisic acid sensitivity during seed germination and seedling growth. We also analyzed the levels of hydrogen peroxide produced in transgenic plants, and the results show that more hydrogen peroxide is produced in the extracellular space of OsTRXh1 knockdown plants than in wild-type plants, whereas the OsTRXh1 overexpression plants produce less hydrogen peroxide under salt stress. These results show that OsTRXh1 regulates the redox state of the apoplast and influences plant development and stress responses.
IPF1/PDX1 deficiency and beta-cell dysfunction in Psammomys obesus, an animal With type 2 diabetes.

The homeodomain transcription factor IPF1/PDX1 is required in beta-cells for efficient expression of insulin, glucose transporter 2, and prohormone convertases 1/3 and 2. Psammomys obesus, a model of diet-responsive type 2 diabetes, shows markedly depleted insulin stores when given a high-energy (HE) diet. Despite hyperglycemia, insulin mRNA levels initially remained unchanged and then decreased gradually to 15% of the basal level by 3 weeks. Moreover, insulin gene expression was not increased when isolated P. obesus islets were exposed to elevated glucose concentrations. Consistent with these observations, no functional Ipf1/Pdx1 gene product was detected in islets of newborn or adult P. obesus using immunostaining, Western blot, DNA binding, and reverse transcriptase-polymerase chain reaction analyses. Other beta-cell transcription factors (e.g., ISL-1, Nkx2.2, and Nkx6.1) were expressed in P. obesus islets, and the DNA binding activity of the insulin transcription factors RIPE3b1-Act and IEF1 was intact. Ipf1/Pdx1 gene transfer to isolated P. obesus islets normalized the defect in glucose-stimulated insulin gene expression and prevented the rapid depletion of insulin content after exposure to high glucose. Taken together, these results suggest that the inability of P. obesus islets to adapt to dietary overload, with depletion of insulin content as a consequence, results from IPF1/PDX1 deficiency. However, because not all animals become hyperglycemic on HE diet, additional factors may be important for the development of diabetes in this animal model.
Effects of Commonly Administered Agents and Genetics on Nebivolol Pharmacokinetics: Drug‐Drug Interaction Studies

Drug interactions are a significant clinical concern, particularly in patients with conditions such as heart disease and hypertension, in whom coadministration of multiple drugs is common. Nebivolol is a selective β1‐blocker with vasodilatory properties approved for the treatment of hypertension. Drug‐drug interactions were investigated when nebivolol was coadministered to subjects classified as poor CYP2D6 metabolizers and extensive CYP2D6 metabolizers who were receiving other drugs commonly administered to patients with hypertension or compounds metabolized by cytochrome P450 (CYP) 2D6. There were no drug‐drug interactions when nebivolol was coadministered with hydrochlorothiazide, furosemide, ramipril, losartan, digoxin, or warfarin. Coadministration with fluoxetine (also metabolized by CYP2D6) in extensive CYP2D6 metabolizers impeded the apparent clearance of nebivolol. The authors conclude that nebivolol is safe and well tolerated regardless of genotype and type of medication coadministered.
What you see is what you want to see: Motivationally relevant stimuli can interrupt current resource allocation

ABSTRACT Arousing stimuli, either threat-related or pleasant, may be selected for priority at different stages within the processing stream. Here we examine the pattern of processing for non-task-relevant threatening (spiders: arousing to some) and pleasant stimuli (babies or chocolate: arousing to all) by recording the gaze of a spider Fearful and Non-fearful group while they performed a simple “follow the cross” task. There was no difference in first saccade latencies. Saccade trajectories showed a general hypervigilance for all stimuli in the Fearful group. Saccade landing positions corresponded to what each group would find arousing, such that the Fearful group deviated towards both types of images whereas the Non-fearful group deviated towards pleasant images. Secondary corrective saccade latencies away from threat-related stimuli were longer for the Fearful group (difficulty in disengaging) compared with the Non-fearful group. These results suggest that attentional biases towards arousing stimuli may occur at different processing stages.
Scale-up and Modeling of Fixed-Bed Reactors for Catalytic Phenol Oxidation over Adsorptive Active Carbon

The wet air oxidation of phenol over a commercial active carbon catalyst has been studied in laboratory-scale and pilot-plant fixed-bed reactors at mild temperatures and oxygen partial pressures of 120−160 °C and 0.05−0.2 MPa, respectively. The performances of the fixed-bed reactors have been assessed and compared to each other for both up- and downflow operation mode. Depending on the flow mode and reactor scale, distinct phenol destruction rates have been observed in the experiments. A series of batch experiments are carried out to obtain phenol removal kinetics, which are subsequently implemented in the modeling of the pilot-plant fixed-bed reactor. A one-dimensional, nonisothermal piston dispersion model is developed to describe in detail the interplay of reaction kinetics, gas−liquid hydrodynamics, and heat and mass transfer in both flow directions. The model predicts reasonably well the experimental data, thus allowing for a thorough explanation of the observed pilot-plant reactor performance.