Miracle-dz/UniFAR-FTUs huggingface dataset:
Profiling Induction of Cytochrome P450 Enzyme Activity by Statins Using a New Liquid Chromatography-Tandem Mass Spectrometry Cocktail Assay in Human Hepatocytes

Human hepatocytes in primary culture are a very useful model to directly assess induction of gene expression by xenobiotics. We developed a cytochrome P450 (P450) activity cocktail assay using model substrates for the seven important P450s 1A2 (phenacetin), 2B6 (bupropion), 2C8 (amodiaquine), 2C9 (tolbutamide), 2C19 (S-mephenytoin), 2D6 (propafenone), and 3A4 (atorvastatin). Metabolite formation was determined by liquid chromatography-tandem mass spectrometry in hepatocyte culture supernatants. Atorvastatin has not been previously assessed as a CYP3A probe drug. We demonstrate highly selective atorvastatin ortho-hydroxylation by CYP3A4 by recombinant P450s. In human liver microsomes ortho-hydroxyatorvastatin formation was highly correlated with CYP3A4 protein content (rs = 0.78, p < 0.0001, n = 150). We profiled induction of these P450 activities in primary human hepatocytes after treatment with 30 μM atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin for 24 to 72 h. Except for pravastatin, all statins induced P450 activities to various degrees, approximately in the order atorvastatin > simvastatin > lovastatin > rosuvastatin. Inducibility of P450s followed the order CYP2C8 > CYP3A4 > CYP2C9 > CYP2B6 > CYP2C19 ∼ CYP2D6 > CYP1A2. The strongest induction was observed for amodiaquine N-desalkylation, which was induced approximately 20-fold. Quantitative reverse transcription-polymerase chain reaction confirmed corresponding changes on the mRNA level with even more dramatic induction up to almost 100-fold. These data suggest a broader inducing effect of statins on cytochrome P450s and possibly other absorption, distribution, metabolism, and excretion genes than previously known, thus further emphasizing their drug-drug interaction potential. Our cocktail assay should be helpful for economical use of human hepatocytes in the assessment of P450 induction by drugs and drug candidates.
Role and Importance of Phenoloxidase in Insect Hemostasis

In response to microbial infection, insects mount several defense reactions including the induction of proteolytic cascades that lead to localized melanization and coagulation. Melanization requires the activation of prophenoloxidase (proPO) to its active form phenoloxidase (PO), a key enzyme that leads to the formation of melanin at wound sites and around intruding microorganisms in the hemolymph. Clotting is critical in limiting hemolymph loss and initiating wound healing following injury; it quickly acts to form a solid barrier against infection by immobilizing microorganisms and promoting their killing. Recent advances in Drosophila and other insects imply a possible link between PO and the coagulation system, although the exact molecular mechanisms controlling this interaction appear to be complex and are still not well defined. The development of hemolymph experimental techniques in Drosophila larvae together with proteomic analysis have further led to the identification of proPO as a cross-linking component that is involved in the hardening and melanization of clots. However, clot PO activity varies between insect species and life stages, depending on physiological and ecological conditions. Here we review our current knowledge of the association between PO and coagulation and discuss the implications of the previous findings on insect innate immunity and hemostasis.
Optimization of PET activation studies based on the SNR measured in the 3-D Hoffman brain phantom

This work investigates the noise properties of O-15 water positron emission tomography (PET) images in an attempt to increase the sensitivity of activation studies. A method for computing the amount of noise within a region of interest (ROI) from the uncertainty in the raw data was implemented for three-dimensional (3-D) PET. The method was used to study the signal-to-noise ratio (SNR) of regions-of-interest (ROIs) inside a 3-D Hoffman brain phantom. Saturation occurs at an activity concentration of 2.2 mCi/l, which corresponds to a 75-mCi O-15 water injection into a normal person of average weight. This establishes the upper limit for injections for human brain studies using 3-D PET on the Siemens ECAT 921 EXACT scanner. Data from human brain activation studies on four normal volunteers using two-dimensional (2-D) PET were analyzed. The biological variation was found to be 5% 1-ml ROIs. The variance for a complete activation study was calculated, for a variety of protocols, by combining the Poisson noise propagated from the raw data in the phantom experiments with the biological variation. A protocol that is predicted to maximize the SNR in dual-condition activation experiments while remaining below the radiation safety limit is: ten scans with 45 mCi per injection. The data should not be corrected for random or scatter events since they do not help in the identification of activation sites while they do add noise to the image. Due to the lower noise level of 3-D PET, the threshold for detecting a true change in activity concentration is 10%-20% lower than 2-D PET. Because of this, a 3-D activation experiment using the Siemens 921 scanner requires fewer subjects fur equal statistical power.
Attentional Blink: An Antecedent to Binge Eating Behavior

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A Process Assessment Model for Very Small Software Entities

A new standard for very small software producing entities is emerging. The standard describes processes for project management and software implementation, and assumes that conformance assessments or process assessments are performed. This paper describes development of a novel process assessment model. The work includes analysis of the prospective standard, which provides the basis for definition of a process reference model. The results of this research may be of benefit to process assessors, assessment tool developers, and future development of the standard.
Hyaluronan Oligosaccharides Inhibit Anchorage-independent Growth of Tumor Cells by Suppressing the Phosphoinositide 3-Kinase/Akt Cell Survival Pathway*

Hyaluronan oligosaccharides (molecular weight: ∼2.5 × 103) inhibit growth of several types of tumors in vivo. In vitro, the oligomers inhibit anchorage-independent growth of several tumor cell types. In accordance with this finding, the oligomers also induce apoptosis and stimulate caspase-3 activity under anchorage-independent conditions. Since inhibitors of phosphoinositide 3-kinase (PI 3-kinase) mimic the action of hyaluronan oligomers and since the PI 3-kinase/Akt (protein kinase B) cell survival pathway has previously been implicated in anchorage-independent growth of tumor cells, we examined the effect of oligomers on PI 3-kinase and its downstream activities in TA3/St murine mammary carcinoma and HCT 116 human colon carcinoma cells. We observed that 50–150 μg/ml hyaluronan oligomers inhibit PI 3-kinase activity and phosphorylation of Akt to approximately the same extent as optimal doses of wortmannin and LY294002, known inhibitors of PI 3-kinase. Similar inhibition of downstream events, i.e.phosphorylation of BAD and FKHR, was also observed. These effects were not observed on treatment with similar concentrations of chitin oligomers, chondroitin sulfate, or hyaluronan polymer. High molecular weight (∼2 × 106) and low molecular weight (∼8 × 104) preparations of hyaluronan polymer were equally ineffective. The effects of hyaluronan oligomers on these parameters were similar in magnitude to the effect of treatment with activity-blocking antibody against CD44. We interpret these results to indicate that the oligomers competitively block binding of endogenous hyaluronan polymer to CD44, consequently giving rise to attenuated signaling. Finally, we observed that hyaluronan oligomers, but not chitin oligomers, chondroitin sulfate, or hyaluronan polymer, stimulate expression of PTEN, a phosphatase that degrades the major signaling product of PI 3-kinase action, phosphoinositide 3,4,5-trisphosphate. We conclude that perturbation of hyaluronan-CD44 binding leads to suppression of the PI 3-kinase/Akt cell survival pathway and consequently to inhibition of anchorage-independent growth in culture and tumor growth in vivo.
Adipose-Derived Mesenchymal Stem Cell Administration Does Not Improve Corneal Graft Survival Outcome

The effect of local and systemic injections of mesenchymal stem cells derived from adipose tissue (AD-MSC) into rabbit models of corneal allograft rejection with either normal-risk or high-risk vascularized corneal beds was investigated. The models we present in this study are more similar to human corneal transplants than previously reported murine models. Our aim was to prevent transplant rejection and increase the length of graft survival. In the normal-risk transplant model, in contrast to our expectations, the injection of AD-MSC into the graft junction during surgery resulted in the induction of increased signs of inflammation such as corneal edema with increased thickness, and a higher level of infiltration of leukocytes. This process led to a lower survival of the graft compared with the sham-treated corneal transplants. In the high-risk transplant model, in which immune ocular privilege was undermined by the induction of neovascularization prior to graft surgery, we found the use of systemic rabbit AD-MSCs prior to surgery, during surgery, and at various time points after surgery resulted in a shorter survival of the graft compared with the non-treated corneal grafts. Based on our results, local or systemic treatment with AD-MSCs to prevent corneal rejection in rabbit corneal models at normal or high risk of rejection does not increase survival but rather can increase inflammation and neovascularization and break the innate ocular immune privilege. This result can be partially explained by the immunomarkers, lack of immunosuppressive ability and immunophenotypical secretion molecules characterization of AD-MSC used in this study. Parameters including the risk of rejection, the inflammatory/vascularization environment, the cell source, the time of injection, the immunosuppression, the number of cells, and the mode of delivery must be established before translating the possible benefits of the use of MSCs in corneal transplants to clinical practice.
Tuning macroscopic body interactions by manipulation of quantum vacuum photon-modes at the nanoscale

We report on a comprehensive theoretical study of a nanostructured cavity system in which we manipulate quantum vacuum photon modes in order to tune the force between cavity boundaries from attractive to repulsive. The presented concept reveals the link between macroscopic forces and the light-matter quantum interactions at the nanoscale. As a case study, the potential interaction energy between a nanopatterned polyethylene slab and a flat polyethylene slab forming a cavity, with a fluid as intervening medium, is calculated. Extremely small corrugations heights appear to be able to turn the interfacial force from attractive to repulsive. This new approach could boost the devices engineering for various applications in surface science.
Left Ventricular Dysfunction With Pulmonary Hypertension: Part 2: Prognosis, Noninvasive Evaluation, Treatment, and Future Research

Pulmonary hypertension (PH) secondary to left-sided heart disease (Group 2 PH) is a frequent complication of heart failure (HF) that worsens exercise capacity, risk for hospitalization, and survival independent of left-ventricular ejection fraction (LVEF) or stage of HF. Increased pulmonary artery pressure (PAP) in patients with HF often represents a combination of increased left-sided filling pressures (passive component) and elevated pulmonary vascular resistance (PVR) attributable to functional and structural abnormalities of the pulmonary vascular bed (reactive component). The latter may be reversible with standard HF treatment in the earlier stages, when remodeling of the pulmonary vasculature has not set in, and abnormalities in pulmonary arterial tone are the major driver for elevated PVR. However, chronic exposure to elevated pulmonary capillary wedge pressure (PCWP) may lead to permanent changes in the pulmonary arterial bed (irreversible or fixed PH). 1 Considering that a number of drug classes have successfully modified the natural history of pulmonary arterial hypertension (Group 1 PH) and demonstrated that intervention is possible even after pulmonary vascular remodeling has occurred,2 Group 2 PH is a natural target for screening and potential intervention in patients with HF. In the second part of this 2-part review, we discuss the prognostic impact of PH in HF, the contemporary diagnostic and evaluation approaches, the current evidence from clinical studies in Group 2 PH, the challenges of appropriate patient selection in clinical trials, and potential ways to overcome these challenges in trial designs. ### Echocardiographic Studies Studies using either right heart catheterization (RHC) or echocardiography for determination of PAP have consistently shown that PH considerably worsens prognosis in HF. Abramson et al3 first reported that tricuspid regurgitation jet velocity >2.5 m/s was associated with 3.4 times higher mortality in 108 patients with dilated cardiomyopathy followed for up to 28 months; hospitalization rate for HF was …
Some(what) grand challenges for information retrieval

Although we see the positive results of information retrieval research embodied throughout the Internet, on our computer desktops, and in many other aspects of daily life, at the same time we notice that people still have a wide variety of difficulties in finding information that is useful in resolving their problematic situations. This suggests that there still remain substantial challenges for research in IR. Already in 1988, on the occasion of receiving the ACM SIGIR Gerard Salton Award, Karen Spärck Jones suggested that substantial progress in information retrieval was likely only to come through addressing issues associated with users (actual or potential) of IR systems, rather than continuing IR research's almost exclusive focus on document representation and matching and ranking techniques. In recent years it appears that her message has begun to be heard, yet we still have relatively few substantive results that respond to it. In this paper, I identify and discuss a few challenges for IR research which fall within the scope of association with users, and which I believe, if properly addressed, are likely to lead to substantial increases in the usefulness, usability and pleasurability of information retrieval.
Modulation of human cardiac function through 4 beta-adrenoceptor populations.

In human heart there is now evidence for the involvement of four beta-adrenoceptor populations, three identical to the recombinant beta 1-, beta 2- and beta 3-adrenoceptors, and a fourth as yet uncloned putative beta-adrenoceptor population, which we designate provisionally as the cardiac putative beta 4-adrenoceptor. This review described novel features of beta-adrenoceptors as modulators of cardiac systolic and diastolic function. We also discuss evidence for modulation by unoccupied beta 1- and beta 2-adrenoceptors. Human cardiac and recombinant beta 1- and beta 2-adrenoceptors are both mainly coupled to adenylyl cyclase through Gs protein, the latter more tightly than the former. Activation of both human beta 1- and beta 2-adrenoceptors not only increases cardiac force during systole but also hastens relaxation through cyclic AMP-dependent phosphorylation of phospholamban and troponin 1, thereby facilitating diastolic function. Furthermore, both beta 1 and beta 2-adrenoceptors can mediate experimental arrhythmias in human cardiac preparations elicited by noradrenaline and adrenaline. Human ventricular beta 3-adrenoceptors appear to be coupled to a pertussis toxin-sensitive protein (Gi? ). beta 3-Adrenoceptor-selective agonists shorten the action potential and cause cardiodepression, suggesting direct coupling of a Gi protein to a K+ channel. In a variety of species, including man, cardiac putative beta 4-adrenoceptors mediate cardiostimulant effects of non-conventional partial agonists, i.e. high affinity beta 1- and beta 2-adrenoceptor blockers that cause agonist effects at concentrations considerably higher than those that block these receptors. Putative beta 4-adrenoceptors appear to be coupled positively to a cyclic AMP-dependent cascade and can undergo some desensitisation.
Training effects in mice after long-term voluntary exercise.

BACKGROUND Mice are an important animal model in exercise studies on the immune system, cancer, and aging. There is limited research about the training effects of long-term voluntary exercise in this species. PURPOSE To describe the training effects in mice given long-term aerobic voluntary exercise. METHODS Female C57BL/6 mice were randomly assigned to 1) individual cages with in-cage running wheels with 24-h access (WR; N = 31), or 2) individual cages without running wheels for 16 wk (NR; N = 20). Run-to-exhaustion (RTE) times, VO2peak, speed at VO2peak, and citrate synthase (CS), succinate dehydrogenase (SDH), and phosphofructokinase (PFK) activity in the soleus, plantaris, and red and white gastrocnemius were assessed. RESULTS Final body weight and speed at VO2peak did not differ by training condition. WR mice had significantly longer RTE times (P < 0.001) and higher VO2peak (P < 0.05) compared with NR mice. Higher CS and SDH activities were found in WR compared with NR mice for soleus (P < 0.01), red gastrocnemius (P < 0.01), and plantaris (P < 0.01) muscles. PFK activity was higher in WR mice in white gastrocnemius compared with NR mice (P < 0.01). CONCLUSIONS Voluntary running wheel activity for 16 wk in female C57BL/6 mice resulted in longer run times to exhaustion, higher VO2peak, and higher SDH and CS activities in oxidative muscles. These findings suggest that wheel running in female C57BL/6 mice: 1) produces a measurable aerobic training effect and 2) is an effective exercise modality for long-term training studies.
Inhibition of proteolytic, serpinolytic, and progelatinase-b activation activities of periodontopathogens by doxycycline and the non-antimicrobial chemically modified tetracycline derivatives.

BACKGROUND Tetracyclines, particularly doxycycline (Doxy), and their non-antimicrobial chemically-modified derivatives (CMTs) inhibit the activities of human matrix metalloproteinases (MMPs), and reduce the severity and progression of periodontal disease in animal models and humans. In this study, the effects of Doxy and CMT-1, -3, and -5 on proteolytic, serpinolytic, and progelatinase-B activation activities of potent periodontopathogens were studied. METHODS The effect of Doxy and CMTs (0.5 to 50 microM) on proteolytic activities were investigated by incubating bacteria with chromogenic substrates or human serum albumin. A collagenolytic fraction of Porphyromonas gingivalis was used to evaluate the effect of these substances on collagenolytic (type I collagen) and serpinolytic (alpha1-proteinase inhibitor) activities. Lastly, the effect of Doxy on progelatinase-B (pro-MMP-9) activation by purified proteinases from P. gingivalis and Treponema denticola was investigated by SDS-PAGE/Western immunoblotting. RESULTS Doxy and CMTs, except CMT-5 which lacks the structural elements required for cation chelation, inhibited Arg- and Lys-gingipain activities as well as collagenolytic activity of P. gingivalis. Doxy and CMTs did not markedly affect the chymotrypsin-like activity of T. denticola but inhibited its trypsin-like activity. In addition, degradation of human serum albumin by cells of P. gingivalis and T. denticola was strongly inhibited by Doxy and CMT-1. Doxy and CMT-1 also inhibited the inactivation of alpha1-proteinase inhibitor (serpinolytic activity) by a collagenolytic fraction of P. gingivalis. Lastly, Doxy prevented the latent to active conversion of human neutrophil progelatinase-B (pro-MMP-9) by Arg-gingipains A/B of P. gingivalis but not by the chymotrypsin-like proteinase of T. denticola. CONCLUSIONS Data from this study suggest that Doxy and CMTs have the potential to inhibit the periodontopathogenic bacterial proteinases, which contribute to tissue destruction cascades during periodontitis directly and indirectly by triggering the host response.
FRET imaging in living maize cells reveals that plasma membrane aquaporins interact to regulate their subcellular localization

Zea mays plasma membrane intrinsic proteins (ZmPIPs) fall into two groups, ZmPIP1s and ZmPIP2s, that exhibit different water channel activities when expressed in Xenopus oocytes. ZmPIP1s are inactive, whereas ZmPIP2s induce a marked increase in the membrane osmotic water permeability coefficient, Pf. We previously showed that, in Xenopus oocytes, ZmPIP1;2 and ZmPIP2;1 interact to increase the cell Pf. Here, we report the localization and interaction of ZmPIP1s and ZmPIP2s in living maize cells. ZmPIPs were fused to monomeric yellow fluorescent protein and/or monomeric cyan fluorescent protein and expressed transiently in maize mesophyll protoplasts. When expressed alone, ZmPIP1 fusion proteins were retained in the endoplasmic reticulum, whereas ZmPIP2s were found in the plasma membrane. Interestingly, when coexpressed with ZmPIP2s, ZmPIP1s were relocalized to the plasma membrane. Using FRET/fluorescence lifetime imaging microscopy, we demonstrated that this relocalization results from interaction between ZmPIP1s and ZmPIP2s. Immunoprecipitation experiments provided additional evidence for the association of ZmPIP1;2 and ZmPIP2;1 in maize roots and suspension cells. These data suggest that PIP1–PIP2 interaction is required for in planta PIP1 trafficking to the plasma membrane to modulate plasma membrane permeability.
Landscape response to climate change: Insights from experimental modeling and implications for tectonic versus climatic uplift of topography

We present the results of an experimental investigation of the concurrent action of tectonic uplift and climate variation on relief evolution. We designed an experimental apparatus that allows the study of erosion of laboratory-scale topographies that evolve under given uplift and rainfall rates. For constant uplift and rainfall rates, the experimental topography evolves toward a statistical steady state defined by a mean elevation constant with time. Starting from such a steady state and keeping the input uplift rate constant, a subsequent change in the rainfall rate yields a change in the mean elevation of the landscape to a new equilibrium elevation. An increase in precipitation yields a lower mean steady-state elevation, whereas for a decrease in precipitation the surface is uplifted. We define this phenomenon as a climatically induced surface uplift, as opposed to a tectonically induced surface uplift. The climatically and tectonically induced surface uplifts correspond to different dynamics of denudation so that it is theoretically possible to differentiate between the climatic or tectonic causes of surface uplift from records of output sediment fluxes.