gebhart/patrepeval huggingface dataset:
Heterodimerization of the erbB-1 and erbB-2 receptors in human breast carcinoma cells: a mechanism for receptor transregulation (1990)

The erbB-1 and erbB-2 protooncogenes encode homologous membrane receptors that respectively bind epidermal growth factor (EGF) and a still incompletely characterized ligand. Binding of EGF to its receptor is known to increase tyrosine phosphorylation of the erbB-2/neu receptor in tumor cells. To investigate the mechanism of this transregulatory pathway, we analyzed the interactions between the two receptors in SKBR-3 human breast carcinoma cells. Chemical cross-linking of 125I-labeled EGF revealed that the radiolabeled EGF receptor coimmunoprecipitates with the erbB-2/neu receptor. In addition a cross-linked species of 360-kdalton molecular mass is also coimmunoprecipitated. The formation of the latter species is absolutely dependent on the presence of EGF receptor and thus appears to represent a heterodimer of the erbB-1 and erbB-2 receptors. In vitro kinase reaction assays revealed that receptor heterodimerization is induced by EGF binding and leads to a dramatic increase in the self-phosphorylation capacity of the dimerized receptors. Moreover, analysis of living SKBR-3 cells suggested that most of the EGF-induced transregulation of the erbB-2/neu receptor is due to receptor heterodimerization. In conclusion, heterodimers of erbB-1 and erbB-2 receptors may provide a mechanism for dual transductory functions of growth factors of breast tumor cells.
Pharmaceutical profiling in drug discovery for lead selection (2004)

Absorption Prediction.- Predicting Molecular Physical Properties.- In Silico Transporter Modeling and Its Application in Drug Discovery.- Models for Cytochrome P450-Mediated Metabolism.- Future of In Silico Methods in Toxicology.- Solubility in Water and DMSO: Issues and Potential Solutions.- Measurements of Lipophilicity and Acid/Base Character Using HPLC Methods.- How Do We Study Oxidative Chemical Stability in Discovery? Some Ideas, Trials, and Outcomes.- Physiochemical Methods for Estimating Permeability and Related Properties.- Cultured Epithelial Cell Assays Used to Estimate Intestinal Absorption Potential.- In Vitro Cell-based Assays for Estimating the Effects of Efflux Transporters on Cell Permeation.- In Vitro Models for Estimating Hepatobiliary Clearance.- Challenges in Drug Discovery: Lead Optimization and Prediction of Human Pharmacokinetics.- Free Drug! The Critical Importance of Plasma Protein Binding in NewDrug Discovery.- Use of In Vitro ADME Screens to Develop Orally Bioavailable and CNS-Permeable Neuropeptide Y Y5 Antagonists.- Applying Computational and In Vitro Approaches to Lead Selection.- Strategies for In Silico and Experimental Screening of Physiochemical Properties.- The Challenge of Quality in Candidate Optimization.- A Comprehensive Strategy for ADME Screening in Drug Discovery.- Scientific, Educational, and Communication Issues Associated with Integrating and Applying Drug-Like Properties in Drug Discovery.
Interleukin-6 Depletion Selectively Improves Hepatic Insulin Action in Obesity (2005)

Obesity and insulin resistance are considered chronic inflammatory states, in part because circulating IL-6 is elevated. Exogenous IL-6 can induce hepatic insulin resistance in vitro and in vivo. The importance of endogenous IL-6, however, to insulin resistance of obesity is unresolved. To test the hypothesis that IL-6 contributes to the inflammation and insulin resistance of obesity, IL-6 was depleted in Lep(ob) mice by injection of IL-6-neutralizing antibody. In untreated Lep(ob) mice, signal transducer and activator of transcription-3 (STAT3) activation was increased compared with that in lean controls, consistent with an inflammatory state. With IL-6 depletion, activation of STAT3 in liver and adipose tissue and expression of haptoglobin were reduced. Expression of the IL-6-dependent, hepatic acute phase protein fibrinogen was also decreased. Using the hyperinsulinemic-euglycemic clamp technique, insulin-dependent suppression of endogenous glucose production was 89% in IL-6-depleted Lep(ob) mice, in contrast to only 32% in Lep(ob) controls, indicating a marked increase in hepatic insulin sensitivity. A significant change in glucose uptake in skeletal muscle after IL-6 neutralization was not observed. In a direct comparison of hepatic insulin signaling in Lep(ob) mice treated with anti-IL-6 vs. IgG-treated controls, insulin-dependent insulin receptor autophosphorylation and activation of Akt (pSer473) were increased by nearly 50% with IL-6 depletion. In adipose tissue, insulin receptor signaling showed no significant change despite major reductions in STAT3 phosphorylation and haptoglobin expression. In diet-induced obese mice, depletion of IL-6 improved insulin responsiveness in 2-h insulin tolerance tests. In conclusion, these results indicate that IL-6 plays an important and selective role in hepatic insulin resistance of obesity.
Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5-lipoxygenase—activating protein inhibitor (1994)

The pharmacodynamics, kinetics, and tolerability of a new orally active 5-lipoxygenase inhibitor were evaluated in healthy male volunteers. MK-0591, 50, 125, and 250 mg every morning and 250 mg every 12 hours, was administered for 10 days. Leukotriene B4 biosynthesis ex vivo in ionophore (A23187)-stimulated whole blood and leukotriene E4 levels in urine were determined. Leukotriene B4 production was inhibited up to 90% of baseline for 12 hours after administration at the highest dose. The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK-0591 concentrations (0 to 1500 ng/ml; r = 0.73). Urinary leukotriene E4 was inhibited by > 80% at 24 hours after administration for all dose levels. Pharmacokinetics of MK-0591 were linear, with a half-life of approximately 6 hours. Very little accumulation was seen after multiple dosing. MK-0591 had no effect on testosterone levels, and good tolerability was shown at all dose levels of MK-0591 administered for up to 10 days.
EPA-1659 – Repeated S-ketamine infusions in treatment-resistant depression (2014)

Ketamine, an N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in individuals with treatmentresistant depression. However, most trials using ketamine were limited to single administration and were performed with the racemic mixture of ketamine. The aim of this case series was to investigate the clinical efficacy of multiple intravenous administrations of S-ketamine in the acute treatment of treatment-resistant depression. In 6 patients suffering from Major Depression (DSM-IV criteria) and being pharmacoresistant to at least 2 antidepressants, intravenous Ketamine treatment was started with a 40 minute administration of 0.25 mg S-ketamine/kg body weight i.v. The treatment was performed over 3 weeks using 2 infusions per week. Patients were kept on their current pharmacotherapy regimen (including antidepressants). The patients were rated using the 21-item version of the Hamilton rating scale for depression (HAMD-21) before and 120 minutes after each ketamine infusion. In 5 of 6 patients a strong improvement of depressive symptoms occurred already after the first ketamine infusion. The response could be stabilized by the following infusions. In 2 patients dissociative symptoms could be seen. Multiple administrations of ketamine appear to be well tolerated, although negative effects on cognition have been described after longer use. The occurrence of dissociative symptoms in two patients in our study must be viewed as an unpleasant side effect. In the literature there is some evidence, that S-ketamine has better tolerability than racemic ketamine but similar antidepressant effects.Download : Download full-size imageDownload : Download full-size image
Toxins which Activate Guanylate Cyclase: Heat‐Stable Enterotoxins (1985)

Certain enteropathogenic bacteria, including strains of Escherichia coli, Klebsiella pneumoniae and Yersinia enterocolitica, elicit their diarrhoeagenic effects by elaborating small molecular weight, heat-stable enterotoxins (STs). Structural and functional characteristics indicate that ST peptides are heterogeneous and two major subtypes, STa and STb, have been identified. Molecules of STa, unlike those of STb, are methanol-soluble and elicit their pathogenic effects by activating host cell guanylate cyclase activity and thereby increasing tissue cyclic GMP content: this increase in cyclic GMP causes fluid secretion. STa binds to specific proteinaceous receptors on intestinal cells but the nature of STa-receptor coupling to guanylate cyclase is poorly understood. The actions of STa, including binding to its receptor, activation of guanylate cyclase and stimulation of electrolyte transport, are rapid, reversible and tissue-specific. STa activates only particulate and not soluble guanylate cyclase. It alters the Vmax but not the apparent Km of this enzyme for Mg-GTP or Mn-GTP. At concentrations above 0.5-1 mM, calcium inhibits the STa activation of guanylate cyclase. The effects of calmodulin antagonists such as chlorpromazine on the activation of guanylate cyclase by STa are less clear. Inhibitors of phospholipid and arachidonic acid cascade pathways interfere with both basal and STa-stimulated guanylate cyclase. Membrane integrity is essential for STa activation of guanylate cyclase and the STa-receptor complex may activate the enzyme by intramembrane protein-protein interactions and/or perturbations. Interference with membrane phospholipid could alter such coupling.
Electrically active axons degenerate when exposed to nitric oxide (2001)

Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vivo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders.
??9-Tetrahydrocannabinol, 11-Hydroxy-??9-Tetrahydrocannabinol and 11-Nor-9-Carboxy-??9-Tetrahydrocannabinol in Human Plasma After Controlled Oral Administration of Cannabinoids (2006)

A clinical study to investigate the pharmacokinetics and pharmacodynamics of oral tetrahydrocannabinol was performed. This randomized, double-blind, placebo-controlled, within-subject, inpatient study compared the effects of THC-containing hemp oils in liquid and capsule form to dronabinol (synthetic THC) in doses used for appetite stimulation. The National Institute on Drug Abuse Institutional Review Board approved the protocol and each participant provided informed consent. Detection times and concentrations of THC, 11-hydroxy-Delta-tetrahydrocannabinol (11-OH-THC), and 11-nor-9-carboxy-Delta-tetrahydrocannabinol (THCCOOH) in plasma were determined by gas chromatography-mass spectrometry [limits of quantification (LOQ)=0.5, 0.5, and 1.0 ng/mL, respectively] after oral THC administration. Six volunteers ingested liquid hemp oil (0.39 and 14.8 mg THC/d), hemp oil in capsules (0.47 mg THC/d), dronabinol capsules (7.5 mg THC/d), and placebo. Plasma specimens were collected during and after each dosing condition. THC and 11-OH-THC concentrations were low and never exceeded 6.1 ng/mL. Analytes were detectable 1.5 hour after initiating dosing with the 7.5 mg THC/d regimen and 4.5 hour after starting the 14.8 mg THC/d sessions. THCCOOH was detected 1.5 hour after the first dose, except for the 0.47 mg THC/d session, which required 4.5 hour for concentrations to reach the LOQ. THCCOOH concentrations peaked at 3.1 ng/mL during dosing with the low-dose hemp oils. Plasma THC and 11-OH-THC concentrations were negative for all participants at all doses within 15.5 hours after the last THC dose. Plasma THCCOOH persisted for at least 39.5 hours after the end of dosing and at much higher concentrations (up to 43.0 ng/mL). This study demonstrated that subjects who used high THC content hemp oil (347 mug/mL) as a dietary supplement had THC and metabolites in plasma in quantities comparable to those of patients using dronabinol for appetite stimulation. There was a significant correlation between body mass index and Cmax and body mass index and number of specimens positive for THC and 11-OH-THC.
Local fluid and heat flow near contact lines (1998)

Journal of Fluid Mechanics , vol. 268 (1994), pp. 231–265 It has recently come to our attention that our paper, which describes Marangoni-driven flow near a contact line, overlooks solutions involving a general thermal boundary condition on the free surface (private communication, S. J. Tavener 1997). These new solutions are applicable for non-isothermal flows in a corner region where one boundary is a rigid plane (and either perfectly insulating or perfectly conducting) and the other is a free surface upon which a general thermal boundary condition is applied. We describe these additional solutions below.
Terf/TRIM17 stimulates degradation of kinetochore protein ZWINT and regulates cell proliferation (2011)

Terf/TRIM17 is a tripartite motif protein that has been originally isolated from testis. Terf has been characterized to exhibit an E3 ubiquitin ligase activity and to undergo self-ubiquitination. The cellular function of terf and its substrates, however, remain elusive. In the present study, we performed a yeast two-hybrid screening assay using terf as bait and identified a positive clone coding for ZW10 interacting protein (ZWINT), a known component of the kinetochore complex required for the mitotic spindle checkpoint. Immunoprecipitation and western blot analyses showed that terf interacted with ZWINT and that overexpression of terf caused down-regulation of protein levels of ZWINT in mammalian cells. In addition, the coiled-coil domain of terf was required for the interaction with ZWINT. In a cell growth assay, stable transfection with terf decreased proliferation of MCF7 breast cancer cells. In contrast, the growth rate of MCF7 cells was increased by stable expression of ZWINT. Specific siRNAs targeting terf and ZWINT dampened these negative and positive effects of terf and ZWINT on cell proliferation, respectively. These results suggest that the E3 ubiquitin ligase terf causes protein degradation of ZWINT and negatively regulates cell proliferation.
Delivery of Epitopes by the Salmonella Type III Secretion System for Vaccine Development (1998)

Avirulent strains of Salmonella typhimurium are being considered as antigen delivery vectors. During its intracellular stage in the host, S. typhimurium resides within a membrane-bound compartment and is not an efficient inducer of class I-restricted immune responses. Viral epitopes were successfully delivered to the host-cell cytosol by using the type III protein secretion system of S. typhimurium. This resulted in class I-restricted immune responses that protected vaccinated animals against lethal infection. This approach may allow the efficient use of S. typhimurium as an antigen delivery system to control infections by pathogens that require this type of immune response for protection.
A History of Tissue Expansion (1993)

Tissue expansion is becoming widely used and accepted and its continued use under many circumstances is justified by the experimental and clinical results.
Gas-phase oligosaccharide nonreducing end (GONE) sequencing and structural analysis by reversed phase hplc/mass spectrometry with polarity switching (2009)

Here we describe a technique to obtain all the N-linked oligosaccharide structures from a single reversed-phase (RP) HPLC run using on-line tandem MS in both positive and negative ion modes with polarity switching. Oligosaccharides labeled with 2-aminobenzamide (2AB) were used because they generated good ionization efficiency in both ion polarities. In the positive ion mode, protonated oligosaccharide ions lose sugar residues sequentially from the nonreducing end with each round of MS fragmentation, revealing the oligosaccharide sequence from greatly simplified tandem MS spectra. In the negative ion mode, diagnostic ions, including those from cross-ring cleavages, are readily observed in the MS2 spectra of deprotonated oligosaccharide ions, providing detailed structural information, such as branch composition and linkage positions. Both positive and negative ion modes can be programmed into the same LC/MS experiment through polarity switching of the MS instrument. The gas-phase oligosaccharide nonreducing end (GONE) sequencing data, in combination with the diagnostic ions generated in negative ion tandem MS, allow both sequence and structural information to be obtained for all eluting species during a single RP-HPLC chromatographic run. This technique generates oligosaccharide analyses at high speed and sensitivity, and reveals structural features that can be difficult to obtain by traditional methods.
Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity (2003)

The Tec family member Bruton's tyrosine kinase (Btk) is a cytoplasmic protein tyrosine kinase that transduces signals from the pre-B and B cell receptor (BCR). Btk is involved in pre-B cell maturation by regulating IL-7 responsiveness, cell surface phenotype changes, and the activation of lambda L chain gene rearrangements. In mature B cells, Btk is essential for BCR-mediated proliferation and survival. Upon BCR stimulation, Btk is transphosphorylated at position Y551, which promotes its catalytic activity and subsequently results in autophosphorylation at position Y223 in the Src homology 3 domain. To address the significance of Y223 autophosphorylation and the requirement of enzymatic activity for Btk function in vivo, we generated transgenic mice that express the autophosphorylation site mutant Y223F and the kinase-inactive mutant K430R, respectively. We found that Y223 autophosphorylation was not required for the regulation of IL-7 responsiveness and cell surface phenotype changes in differentiating pre-B cells, or for peripheral B cell differentiation. However, expression of the Y223F-Btk transgene could not fully rescue the reduction of lambda L chain usage in Btk-deficient mice. In contrast, transgenic expression of kinase-inactive K430R-Btk completely reconstituted lambda usage in Btk-deficient mice, but the defective modulation of pre-B cell surface markers, peripheral B cell survival, and BCR-mediated NF-kappaB induction were partially corrected. From these findings, we conclude that: 1) autophosphorylation at position Y223 is not essential for Btk function in vivo, except for regulation of lambda L chain usage, and 2) during B cell development, Btk partially acts as an adapter molecule, independent of its catalytic activity.
An Online Mapping Algorithm for Teams of Mobile Robots (2000)

We propose a new probabilistic algorithm for online mapping of unknown environments with teams of robots. At the core of the algorithm is a technique that combines fast maximum likelihood map growing with a Monte Carlo localizer that uses particle representations. The combination of both yields an online algorithm that can cope with large odometric errors typically found when mapping an environment with cycles. The algorithm can be implemented distributedly on multiple robot platforms, enabling a team of robots to cooperatively generate a single map of their environment. Finally, an extension is described for acquiring three-dimensional maps, which capture the structure and visual appearance of indoor environments in 3D.
Regulatory T cells in patients with inflammatory bowel diseases treated with adacolumn granulocytapheresis (2008)

The clinical efficacy of GMA on IBD and related extra intestinal manifestations was associated with an expansion of circulating CD4+ CD25+ Tregs and higher expression of FoxP3 in CD4+ T cells. Accordingly, an elevated CD4+ CD25+ FoxP3 may be a valuable index of remission in patients with IBD and other chronic relapsing-remitting inflammatory conditions during treatment with GMA.
Stereochemistry of hydrolysis by snake venom phosphodiesterase. (1979)

[18O]Adenosine 5'-O-phosphorothioate-O-p-nitrophenyl ester was prepared by saponification of the bis (-O,O-p-nitrophenyl ester) with K18OH. Only the diastereoisomer with the Rp configuration si a substrate for snake venom phosphodiesterase. The asymmetrically labeled [18O]adenosine 5'-O-phosphorothioate formed in this reaction was converted enzymatically to [18O]adenosine 5'-(1-thiodiphosphate) with the Sp configuration. The position of the 18O label, either bridging [1,2-mu-18O] or nonbridging [1-18O] was then determined. The results show that the reaction catalyzed by snake venom phosphodiesterase takes place with retention of configuration at phosphorus. This indicates that the hydrolysis proceeds via a covalent nucleotide enzyme intermediate.
Paraperm EW lens for extended wear. (1989)

This paper reports the results of 372 patients fit with the Paraperm EW rigid gas permeable lens for extended wear. This lens material is a copolymer derived from siloxane and methylmethacrylate with an oxygen permeability (Dk) of 56 X 10(-11) at 37 degrees C. At the end of 1 year, 270 patients had completed the study with 94.8% achieving 20/25 or better vision. Complications included a 12.3% incidence of superficial limbal keratitis with staining, a 3.1% incidence of conjunctival injection, and a 1.5% incidence of observable corneal edema. The lens appears to be a significant addition to the possibilities available for fitting extended wear patients or those who desire occasional overnight lens wear.
유로화의 국제통화로서의 결정요인에 관한 연구 (2003)

제2차 세계대전 이후 최근까지 국제통화질서는 미국의 달러화 중심체제로 유지되어 왔다. 이러한 미국의 독주에 대응하여 유럽국가들은 1999년 유럽통화동맹(EMU)을 결성하고 2002년 1월 유로화를 단일통화로서 공식적으로 도입하였다. 본 연구는 국제통화로서 가장 중요한 결정요인이 되는 가격안정성과 경제규모에 의해서 유로화를 달러 및 엔화와 비교하면서 현재 국제통화로서 어떠한 위상을 차지하고 있는지 평가하였다. 또한 실증적으로 국제채권시장과 외환시장 및 상품시장에서 유로화의 위상에 대한 자료를 분석하였다. 이 논문의 주요 분석결과는 다음과 같다. 첫째, 어떤 통화가 국제기축통화가 되기 위해서는 두 가지 기본적 조건인 가격안정성과 일정한 경제규모가 충족되어야 하며 유로화는 유로지역을 물리적으로 통합하고 여러 제도를 보완함으로써 이러한 요건을 충족시키고 있다. 특히 이러한 과정에서 유럽중앙은행(ECB)은 통화의 신뢰성을 확보하는 데 가장 중요한 역할을 수행하고 있다는 점을 확인할 수 있었다. 둘째, EMU출범 4년 만에 유로화는 제2의 국제통화로서 성공적으로 정착한 것으로 나타났다. 그러나 여러 면에서 유로의 국제적 역할은 점진적으로 증가하는 것으로 나타나고 있으며 외환보유고와 외환시장에서는 커다란 변화를 발견하기 어려웠다. 이는 주로 아시아 국가들의 중앙은행이 외환보유고를 대부분 달러로 보유한데 기인하는 것으로 판단된다. 셋째, 유로의 국제적 역할은 지역적 특성이 강하게 나타난다는 점을 발견할 수 있었다. 국제통화로서의 유로의 사용은 유로인접국가에서 두드러지게 나타나며 유로의 국제적 역할은 EU와의 무역 및 역사적 연관성을 깊이 지니고 있는 구가에서 강하게 나타나고 있었다. 유로의 이런 지정학적 특성은 전 세계에 광범위하게 통용되는 미국 달러와 극명하게 대조되고 있다. 또한 환율정책에 있어서도 외환준비금으로서의 유로의 역할은 유로인접지역에 국한하여 나타나고 있다. 따라서 국제통화로서 유로가 보다 광범위하게 사용되기 위해서는 아시아와 유럽의 경제협력을 증진시킬 필요가 있다. 특히 최근 외환시장에서 유로화의 강세는 아시아의 중앙은행이 외환리스크를 분산할 필요가 있다는 점을 확인시키는 계기가 될 것이다.