gebhart/patrepeval huggingface dataset:
Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration (2002)

The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring (14)C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and V(d(ss)) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [(14)C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.
Integrins as receptors for laminins (2000)

Laminins are a family of trimeric glycoproteins present in the extracellular matrix and the major constituents of basement membranes. Integrins are alpha beta transmembrane receptors that play critical roles in both cell-matrix and cell-cell adhesion. Several members of the integrin family, including alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, alpha 6 beta 1, alpha 7 beta 1 and alpha 6 beta 4 heterodimers serve as laminin receptors on a variety of cell types. This review summarizes recent advances in understanding the involvement of individual integrins in cell interactions with laminins and the roles of laminin-binding integrins in adhesion-mediated events in vertebrates, including embryonic development, cell migration and tumor cell invasiveness, cell proliferation and differentiation, as well as basement membrane assembly. We discuss the regulation of integrin function via alternative splicing of cytoplasmic domains of alpha and beta subunits of the integrin receptors for laminins and present examples of functional collaboration between laminin-binding integrins and non-integrin laminin receptors. Advances in our understanding of the laminin-binding integrins continue to demonstrate the essential roles these receptors play in maintaining cell polarity and tissue architecture.
ANTENNAL LOBE: New Developments (2000)

The antennal lobe of insects has emerged as an excellent model for olfactory processing in the CNS. In the present review we compile data from areas where substantial progress has been made during recent years: structure-function rela- tionships within the glomerular array, integration and blend specificity, time coding and the effects of neuroactive substances and hormones on antennal lobe processing.
Amyotrophic leteral sclerosis: Part 2. Etiopathogenesis (1985)

The pathogenesis of the motor neuronal degeneration in amyotrophic lateral sclerosis (ALS) is unclear, though several possible etiological factors are currently being investigated. A unifying hypothesis will have to explain the diverse geographical occurrence, clinical features, and selective vulnerability and relative resistance of different neuronal populations in the disease. It is possible that different biochemical defects underlie this diversity, or alternatively that the many factors incriminated in the etiology may act upon an underlying genetic-biochemical abnormality to trigger premature neuronal death. Viruses, metals, endogenous toxins, immune dysfunction, endocrine abnormalities, impaired DNA repair, altered axonal transport, and trauma have all been etiologically linked with ALS, but convincing research evidence of a causative role for any of these factors is yet to be demonstrated.
High bandwidth efficiency space-time turbo coded modulation (2002)

Space-time coding schemes are designed to achieve potentially high capacity offered in MIMO Rayleigh fading channels by exploiting the benefits of spatial and temporal diversity. We propose recursive space-time trellis codes for high bandwidth efficient 8PSK and 16QAM space-time turbo coded modulation. The proposed scheme was designed to preserve the maximum transmit diversity gain but simultaneously enhance the coding gain as compared to Tarokh et al. space-time trellis codes. Puncturing the outputs of component codes enabled a considerable improvement in power efficiency to come with no cost in high bandwidth efficiency. Good performance was reported even with extremely short input information frames.
Computer Simulation of Multilayer Hydraulic Fractures (2000)

Abstract When a hydraulic fracturing treatment is carried out in a layered formation, multiple fractures may propagate simultaneously in different layers. It is important to determine whether the multiple layers can be effectively stimulated in one treatment or if a multi-stage treatment is a better solution. Present fracturing models are mostly adequate to design and evaluate multiple stage treatments. In this paper, a computer simulator of multi-layer fractures is presented with the view of designing and evaluating simultaneous fracturing treatments in layered formations. The simulator rigorously calculates the flow rate distribution into multiple fractures based on mass conservation and pressure continuity principles. The fracture in each layer is treated as a pseudo-three-dimensional (P3D) hydraulic fracture model that allows height growth into adjacent layers. The multiple fractures are inter-related not only by the hydraulics through the wellbore, but also by the mechanical interaction through the rock formation, which is important when the stress barriers between layers are weak and fractures grow close to each other. The fracture growth behavior observed from other geomechanics studies is applied in this model. The results from this simulator and a previous one based on the PKN model are compared and discussed. The importance of fracture height growth on flow rate distribution and propped fracture geometry is demonstrated. Tip screenout and near-wellbore screenout in one or more fractures are simulated, showing flow rate diversion into other fractures after screenout occurs in one fracture. Simulation results also show that perforation erosion may have an undesirable effect on the ratio of slurry volume to pad volume in each fracture. Measured data of pressure and flow rates from a field test are compared with the simulation results and good agreement is observed. Based on the results of the simulator, recommendations on the design of simultaneous fracturing treatments of multiple pay zones are presented.
Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain (2003)

Neuronal nicotinic receptor (NNR) agonists such as ABT 594 have been shown to be effective in a wide range of preclinical models of acute and neuropathic pain. The present study, using the NNR agonist A-85380, sought to determine if NNR agonists are acting via similar or differing mechanisms to induce anti-nociception and anti-allodynia. A systemic administration of the quaternary NNR antagonist chlorisondamine (0.4 micromol/kg, intraperitoneal (i.p.)) did not alter A-85380-induced (0.75 micromol/kg, i.p.) anti-nociception in the rat paw withdrawal model of acute thermal pain. In contrast, previous studies have demonstrated that blockade of central NNRs by prior administration of chlorisondamine (10 microg i.c.v.) prevents A-85380 induced anti-nociception indicating a predominantly central site of action of NNR agonists in relieving acute pain. In the rat spinal nerve ligation model of neuropathic pain, A-85380 induced a dose-dependent anti-allodynia (0.5-1.0 micromol/kg) that was blocked by pretreatment with mecamylamine (1 micromol/kg). Interestingly, unlike acute pain, both systemic and central administration of chlorisondamine blocked A-85380-induced anti-allodynia, an effect that was determined not to be due to a non-specific effect of chlorisondamine or to chlorisondamine crossing the blood-brain barrier. The peripheral site of action was shown not to be the primary receptive field, since A-85380 had equally potent anti-allodynic effects when it was injected into either the affected or unaffected paw. In contrast, infusion of A-85380 directly onto the L5 dorsal root ganglion on the affected side resulted in a dose-dependent and marked anti-allodynia (10-20 microg) at doses that had no effect when injected systemically. This effect was blocked by pretreatment with chlorisondamine. Together these data further support the idea that different mechanisms underlie different pain states and suggest that the effects of NNR agonists in neuropathic pain may be due in part to peripheral actions of the compounds.
Identification of a neural-specific cDNA, NPDC-1, able to down-regulate cell proliferation and to suppress transformation. (1995)

Immortalized neural precursor cell lines carrying the polyoma large tumor (T) gene have been shown previously to retain a clear-cut contact inhibition of growth and to differentiate in vitro. In the present study, we have identified and isolated cDNA clones corresponding to RNA expressed preferentially when these cells reach confluence. One of them, NPDC-1, is expressed specifically in the nervous system. The transfection of dividing cells with a NPDC-1 expression vector results in the inhibition of cell proliferation. In addition, the stable introduction of NPDC-1 into transformed cells, even of nonneural origin, leads to the suppression of transformed characteristics.
A New Parametric Approach to Modeling Generalized AutoregressiveConditional Density Model at Higher Order Moments (2003)

This paper presents a flexible Autoregressive Conditional Density Moments-in-Mean (ARCD Moments-in-Mean) model. Our innovative approach not only allow the higher order moments to be time-varying function of conditioning information, but also extend the traditional ARCH-M model by explicitly modeling the influence of conditional moments (conditional variance, skewness and kurtosis) on the conditional expectation of the data series. The empirical results suggest a preponderance of evidence to support the performance of ARCD Moments-in-Mean model on competing alternatives. Of particular, the time varying skewness, capturing the up/downside risk, is found to exhibit significant effect in explaining the expected return than that of second and fourth moment. In addition, it is also found that the asymmetry of conditional distribution is potentially possible to substitute the asymmetry in the volatility specification, demonstrating the importance to specify the proper distribution specification on financial econometric modeling.

Keywords: GARCH model, skewness, kurtosis, moments, risk premium, distribution.
Genetic Evidence That the Differential Expression of the Ligand-Independent Isoform of CTLA-4 Is the Molecular Basis of the Idd5.1 Type 1 Diabetes Region in Nonobese Diabetic Mice (2009)

Idd5.1 regulates T1D susceptibility in nonobese diabetic (NOD) mice and has two notable candidate genes, Ctla4 and Icos. Reduced expression of one of the four CTLA-4 isoforms, ligand-independent CTLA-4 (liCTLA-4), which inhibits in vitro T cell activation and cytokine production similarly to full-length CTLA-4 (flCTLA-4), has been hypothesized to increase type 1 diabetes (T1D) susceptibility. However, further support of this hypothesis is required since the Idd5.1 haplotypes of the diabetes-susceptible NOD and the resistant B10 strains differ throughout Ctla4 and Icos. Using haplotype analysis and the generation of novel Idd5.1-congenic strains that differ at the disease-associated Ctla4 exon 2 single-nucleotide polymorphism, we demonstrate that increased expression of liCTLA-4 correlates with reduced T1D susceptibility. To directly assess the ability of liCTLA-4 to modulate T1D, we generated liCTLA-4-transgenic NOD mice and compared their diabetes susceptibility to nontransgenic littermates. NOD liCTLA-4-transgenic mice were protected from T1D to the same extent as NOD.B10 Idd5.1-congenic mice, demonstrating that increased liCTLA-4 expression alone can account for disease protection. To further investigate the in vivo function of liCTLA-4, specifically whether liCTLA-4 can functionally replace flCTLA-4 in vivo, we expressed the liCTLA-4 transgene in CTLA-4(-/-) B6 mice. CTLA-4(-/-) mice expressing liCTLA-4 accumulated fewer activated effector/memory CD4(+) T cells than CTLA-4(-/-) mice and the transgenic mice were partially rescued from the multiorgan inflammation and early lethality caused by the disruption of Ctla4. These results suggest that liCTLA-4 can partially replace some functions of flCTLA-4 in vivo and that this isoform evolved to reinforce the function of flCTLA-4.
Atlas-Based Quantification of Cardiac Remodeling Due to Myocardial Infarction (2014)

Myocardial infarction leads to changes in the geometry (remodeling) of the left ventricle (LV) of the heart. The degree and type of remodeling provides important diagnostic information for the therapeutic management of ischemic heart disease. In this paper, we present a novel analysis framework for characterizing remodeling after myocardial infarction, using LV shape descriptors derived from atlas-based shape models. Cardiac magnetic resonance images from 300 patients with myocardial infarction and 1991 asymptomatic volunteers were obtained from the Cardiac Atlas Project. Finite element models were customized to the spatio-temporal shape and function of each case using guide-point modeling. Principal component analysis was applied to the shape models to derive modes of shape variation across all cases. A logistic regression analysis was performed to determine the modes of shape variation most associated with myocardial infarction. Goodness of fit results obtained from end-diastolic and end-systolic shapes were compared against the traditional clinical indices of remodeling: end-diastolic volume, end-systolic volume and LV mass. The combination of end-diastolic and end-systolic shape parameter analysis achieved the lowest deviance, Akaike information criterion and Bayesian information criterion, and the highest area under the receiver operating characteristic curve. Therefore, our framework quantitatively characterized remodeling features associated with myocardial infarction, better than current measures. These features enable quantification of the amount of remodeling, the progression of disease over time, and the effect of treatments designed to reverse remodeling effects.
Extreme Sensitivity of Enveloped Viruses, Including Herpes Simplex, to Long-Chain Unsaturated Monoglycerides and Alcohols (1979)

Unsaturated monoglycerides and alcohols of chain lengths of 16 or 18 carbons were found to be extremely potent inactivators of two enveloped viruses, herpes simplex virus type 2 and bacteriophage phi6. The lipid-containing bacteriophage PM2 was also inactivated by some of these amphiphilic molecules. Treatment of herpes simplex virus type 2 with these compounds at concentrations as low as 0.2 muM reduced virus survival to 50% in 30 min, making these agents the most potent inactivators of herpes simplex viruses discovered that are not cytotoxic to mammalian cells. Detailed characterizations of the effects of unsaturated monoglycerides and alcohols on bacteriophages phi6 and PM2 showed that the inactivated phi6 virion remained nearly intact but that PM2 was almost completely disrupted by the inactivating treatment. Some of the compounds inactivate the viruses even at low temperature (0 degrees C). Excess amounts of diglycerides and phospholipids interfere with the inactivating abilities of some of the unsaturated monoglycerides and alcohols against phi6 and PM2. Our findings suggest that the unsaturated monoglycerides and some of the unsaturated alcohols should be further studied as potential antiviral agents, particularly for application to herpesvirus-infected areas of the skin and accessible epithelium.
Dominant TCR-α Requirements for a Self Antigen Recognition in Humans (2002)

TCR-alpha and -beta chains are composed of somatically rearranged V, D, and J germline-encoded gene segments that confer Ag specificity. Recent crystallographic analyses revealed that TCR-alpha has more contacts with peptide than TCR-beta, suggesting the possibility that peptide recognition predominantly relies on TCR-alpha. T cells specific for the self Ag Melan-A/MART-1 possess an exceptionally high precursor frequency in human histocompatibility leukocyte Ag-A2 individuals. This provided a unique situation for assessment of the structural relationship between TCR and peptide/MHC ligand at both the pre- and postimmune levels. Molecular and phenotypic analysis of many different Melan-A-specific T cell populations revealed that a structural constraint is imposed on the TCR for engagement with Melan-A peptides presented by HLA-A2, namely the highly preferential use of a particular TCRAV segment, AV2. Examination of CD8 single-positive thymocytes indicated that this preferential use in forming the Melan-A-specific TCR is mainly imposed by intrathymic positive selection. Our data demonstrate a dominant function of TCRAV2 segment in forming the TCR repertoire specific for the human self Ag Melan-A/MART-1 and support the view that Ag recognition is mediated predominantly by TCR-alpha.
Hidden Problems with the Hidden Node Problem (2006)

We discuss a few problems introduced by the RTS/CTS mechanism of collision avoidance and focus on the virtual jamming problem, which allows a malicious node to effectively jam a large fragment of a wireless network at a minimum expense of power. We propose a solution to this problem and provide experimental data illustrating the impact of virtual jamming and the effectiveness of our proposed solution
Single virus detection from the reactive shift of a whispering-gallery mode (2008)

We report the label-free, real-time optical detection of Influenza A virus particles. Binding of single virions is observed from discrete changes in the resonance frequency/wavelength of a whispering-gallery mode excited in a microspherical cavity. We find that the magnitude of the discrete wavelength-shift signal can be sufficiently enhanced by reducing the microsphere size. A reactive sensing mechanism with inverse dependence on mode volume is confirmed in experiments with virus-sized polystyrene nanoparticles. By comparing the electromagnetic theory for this reactive effect with experiments, the size and mass ( approximately 5.2 x 10(-16) g) of a bound virion are determined directly from the optimal resonance shift.
Serotonin: Synthesis and Release from the Myenteric Plexus of the Mouse Intestine (1965)

After injection of its radioactive precursor, 5-hydroxytryptophan, radioactive serotonin was biosynthesized and bound in the myenteric plexus of the mouse intestine. Addition of nonradioactive serotonin to preparations in vitro caused a net release of radioactive serotonin from the plexus. This release appeared to result from activity in the intramural nervous system of the intestine. A neurotransmitter role between sensory and motor neurons in the peristaltic reflex pathway is suggested as a working hypothesis to explain the action of serotonin.
The effects of administration of mCPP on psychological, cognitive, cardiovascular, hormonal and MHPG measurements in human volunteers (1994)

m-Chlorophenylpiperazine (mCPP) is a metabolite of the antidepressant trazodone which has been widely used in psychopharmacology research as a probe of serotonin (5-hydroxytryptamine; 5-HT) function. However, in addition to binding at 5-HT receptors it also binds strongly to alpha 2-adrenoceptors, and it is conceivable that some of the physical and psychological symptoms previously reported following mCPP infusion are due to effects upon central noradrenergic neurotransmitter function. In this double-blind placebo-controlled balanced-crossover study in 12 healthy male volunteers we have examined the effects of infusion of mCPP (0.08 mg/kg over 2 min) on symptoms of anxiety, cognitive performance, pulse and blood pressure, and plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol, prolactin, growth hormone, and the noradrenaline metabolite 3-methoxy-4-hydroxyphenyl glycerol (MHPG). The results confirm previous findings that in humans mCPP causes significant increases in the symptoms of anxiety, and in the plasma concentrations of cortisol, prolactin and growth hormone. In addition, our results demonstrate that mCPP causes no significant changes in cognitive performance, in pulse or systolic blood pressure, or in the plasma concentration of MHPG. Since pulse, systolic blood pressure and MHPG plasma concentrations all to some degree reflect central noradrenergic activity, we believe it unlikely that the psychological and hormonal effects of mCPP are due primarily to effects on noradrenergic neurotransmission. Further studies to address this specific issue are needed, however, before firm conclusions can be reached.
The effect of verapamil on the restoration of myocardial perfusion and functional recovery in patients with angiographic no-reflow after primary percutaneous coronary intervention (2006)

Intracoronary verapamil restored myocardial perfusion in patients with angiographic no-reflow after PCI and lead to better functional recovery after acute myocardial infarction.
The LRP5 High-Bone-Mass G171V Mutation Disrupts LRP5 Interaction with Mesd (2004)

The mechanism by which the high-bone-mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates canonical Wnt signaling was investigated. The mutation was previously shown to reduce DKK1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for DKK-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperone protein for LRP5/6 that is required for transport of the coreceptors to cell surfaces, resulting in fewer LRP5 molecules on the cell surface. Although the reduction in the number of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine DKK1, we think that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine DKK1 to antagonize without affecting the activity of autocrine Wnt.