gebhart/patrepeval huggingface dataset:
Diethanolamine Induces Hepatic Choline Deficiency in Mice (2002)

The purpose of the present experiments was to test the hypothesis that diethanolamine (DEA), an alkanolamine shown to be hepatocarcinogenic in mice, induces hepatic choline deficiency and to determine whether altered choline homeostasis was causally related to the carcinogenic outcome. To examine this hypothesis, the biochemical and histopathological changes in male B6C3F1 mice made choline deficient by dietary deprivation were first determined. Phosphocholine (PCho), the intracellular storage form of choline was severely depleted, decreasing to about 20% of control values with 2 weeks of dietary choline deficiency. Other metabolites, including choline, glycerophosphocholine (GPC), and phosphatidylcholine (PC) also decreased. Hepatic concentrations of S-adenosylmethionine (SAM) decreased, whereas levels of S-adenosylhomocysteine (SAH) increased. Despite these biochemical changes, fatty liver, which is often associated with choline deficiency, was not observed in the mice. The dose response, reversibility, and strain-dependence of the effects of DEA on choline metabolites were studied. B6C3F1 mice were dosed dermally with DEA (0, 10, 20, 40, 80, and 160 mg/kg) for 4 weeks (5 days/week). Control animals received either no treatment or dermal application of 95% ethanol (1.8 ml/kg). PCho was most sensitive to DEA treatment, decreasing at dosages of 20 mg/kg and higher and reaching a maximum 50% depletion at 160 mg/kg/day. GPC, choline, and PC also decreased in a dose-dependent manner. At 80 and 160 mg/kg/day, SAM levels decreased while SAH levels increased in liver. A no-observed effect level (NOEL) for DEA-induced changes in choline homeostasis was 10 mg/kg/day. Choline metabolites, SAM and SAH returned to control levels in mice dosed at 160 mg/kg for 4 weeks and allowed a 2-week recovery period prior to necropsy. In a manner similar to dietary choline deficiency, no fatty change was observed in the liver of DEA-treated mice. In C57BL/6 mice, DEA treatment (160 mg/kg) also decreased PCho concentrations, without affecting hepatic SAM levels, suggesting that strain-specific differences in intracellular methyl group regulation may influence carcinogenic outcome with DEA treatment. Finally, in addition to the direct effects of DEA on choline homeostasis, dermal application of 95% ethanol for 4 weeks decreased hepatic betaine levels, suggesting that the use of ethanol as a vehicle for dermal application of DEA may exacerbate or confound the biochemical actions of DEA alone. Collectively, the results demonstrate that DEA treatment causes a spectrum of biochemical changes consistent with choline deficiency in mice and demonstrate a clear dose concordance between DEA-induced choline deficiency and hepatocarcinogenic outcome.
MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium (2009)

We have shown that smoking impacts bronchial airway gene expression and that heterogeneity in this response associates with smoking-related disease risk. In this study, we sought to determine whether microRNAs (miRNAs) play a role in regulating the airway gene expression response to smoking. We examined whole-genome miRNA and mRNA expression in bronchial airway epithelium from current and never smokers (n = 20) and found 28 miRNAs to be differentially expressed (P < 0.05) with the majority being down-regulated in smokers. We further identified a number of mRNAs whose expression level is highly inversely correlated with miRNA expression in vivo. Many of these mRNAs contain potential binding sites for the differentially expressed miRNAs in their 3'-untranslated region (UTR) and are themselves affected by smoking. We found that either increasing or decreasing the levels of mir-218 (a miRNA that is strongly affected by smoking) in both primary bronchial epithelial cells and H1299 cells was sufficient to cause a corresponding decrease or increase in the expression of predicted mir-218 mRNA targets, respectively. Further, mir-218 expression is reduced in primary bronchial epithelium exposed to cigarette smoke condensate (CSC), and alteration of mir-218 levels in these cells diminishes the induction of the predicted mir-218 target MAFG in response to CSC. These data indicate that mir-218 levels modulate the airway epithelial gene expression response to cigarette smoke and support a role for miRNAs in regulating host response to environmental toxins.
Capillary Zone Electrophoresis (1987)

Capillary zone electrophoresis is a technique which permits rapid and efficient separations of charged substances in an instrumental format. Buffer-filled capillaries with typical dimensions of 50 microns i.d. and 100 cm length are used as the separation chambers. Applied potentials as high as 30 KVolts are used to drive the electrophoretic process. Such high potentials promote rapid migration of zones, while minimizing zone spreading. A simple theory of zone spreading and resolution is presented. A physical description of the system and some of its operating characteristics is provided. Separating performance of the system is described and example separations shown. Limitations of the system, particularly with regard to the separation of proteins, are discussed and future areas for research are suggested.
Treatments of Parkinson Disease (2003)

Parkinson disease (PD) is a progressive degenerative neurological disorder characterized by resting tremor, bradykinesia, cogwheel rigidity, and postural instability.1 In the later stages, approximately 25% or more of patients develop cognitive compromise. The cardinal pathological features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta and their axons, which project principally to the caudate and putamen, and the presence of eosinophilic intracytoplasmic inclusions, Lewy bodies.2-3 Although the loss of neurons is most conspicuous in the substantia nigra pars compacta, neuronal loss and/or Lewy bodies are found in other brain regions (eg, the locus coeruleus, entorhinal region, and amygdala),2 which suggests that treatments that target only the nigrostriatal dopaminergic system, though they may substantially benefit patients, are unlikely to completely resolve the deficits of PD.
Interaction among autoregulation, CO2 reactivity, and intracranial pressure: a mathematical model (1998)

The relationships among cerebral blood flow, cerebral blood volume, intracranial pressure (ICP), and the action of cerebrovascular regulatory mechanisms (autoregulation and CO2 reactivity) were investigated by means of a mathematical model. The model incorporates the cerebrospinal fluid (CSF) circulation, the intracranial pressure-volume relationship, and cerebral hemodynamics. The latter is based on the following main assumptions: the middle cerebral arteries behave passively following transmural pressure changes; the pial arterial circulation includes two segments (large and small pial arteries) subject to different autoregulation mechanisms; and the venous cerebrovascular bed behaves as a Starling resistor. A new aspect of the model exists in the description of CO2 reactivity in the pial arterial circulation and in the analysis of its nonlinear interaction with autoregulation. Simulation results, obtained at constant ICP using various combinations of mean arterial pressure and CO2 pressure, substantially support data on cerebral blood flow and velocity reported in the physiological literature concerning both the separate effects of CO2 and autoregulation and their nonlinear interaction. Simulations performed in dynamic conditions with varying ICP underline the existence of a significant correlation between ICP dynamics and cerebral hemodynamics in response to CO2 changes. This correlation may significantly increase in pathological subjects with poor intracranial compliance and reduced CSF outflow. In perspective, the model can be used to study ICP and blood velocity time patterns in neurosurgical patients in order to gain a deeper insight into the pathophysiological mechanisms leading to intracranial hypertension and secondary brain damage.
Antibody engineering of recombinant Fv immunotoxins for improved targeting of cancer: disulfide-stabilized Fv immunotoxins. (1996)

Recombinant immunotoxins are chimeric proteins in which a truncated toxin is fused to a recombinant antigen-binding domain such as a recombinant Fv or Fab. Recombinant immunotoxins target cell surface receptors and other antigens on tumor cells. The antigen-binding and -targeting domains in recombinant immunotoxins are usually single-chain Fvs (scFv), which are the antibody variable regions connected by a flexible peptide linker and fused directly to a bacterial toxin. However, Fabs have also been used. Recombinant immunotoxins have very good activity in vitro on cultured human tumor cell lines and have produced complete regressions and cures of established tumor xenografts in nude mouse models. Problems with the stability and binding of some scFv immunotoxins as well as scFvs not linked to toxin led to the development of a new type of recombinant Fv immunotoxin in which the targeting variable domains of the Fv are stabilized by an interchain disulfide bond located in structurally conserved framework positions of the VH and VL domains. These are termed disulfide-stabilized Fvs (dsFv) or dsFv immunotoxins. dsFvs and dsFv immunotoxins have several advantages over scFv immunotoxins. This review summarizes the design, construction, activities in vitro and in vivo, and biochemical characteristics of dsFv immunotoxins and compares them with scFv immunotoxins.
Wellbore Stability in Fractured Rock (2010)

Abstract Numerous wellbore instability problems related to drilling through potentially fractured formations have been reported. Often, these rocks are characterized by the abundance of macro and micro scale bedding planes and/or networks of natural fractures. The presence of fractures weakens the rock mechanically and produces potentially higher-permeability fluid-flow paths within the low-permeability rock matrix. Practically, it is difficult to identify fracture size and fracture density without a costly core sample. A number of wellbore stability case studies have therefore been published where the author relied on anecdotal evidence to postulate failure mechanisms involving fractured rock, and recommendations for how to mitigate the observed instability range from increasing to decreasing the wellbore pressure. This paper presents results from a geomechanical investigation of a wellbore instability incident experienced in a fractured shale formation. As part of this assessment, a preserved core was obtained from the fractured shale interval and the presence of fractures was identified both by CAT scan and visual inspection. A series of triaxial tests were conducted to characterize the mechanical properties and failure strength of this shale. This data, combined with wellbore stability modeling, suggests that the residual strength, rather than the peak failure strength, is a more representative measure of a fractured rock's in-situ strength. The Hoek and Brown (1982) failure criterion was found to be particularly suitable for modeling fractured rock. Multi-arm caliper logs from two boreholes through the same fractured shale suggests that wellbore instability is more complex in the fractured interval than in the over- and underlying intact rock. These caliper logs also clearly demonstrate that the borehole quality was significantly improved by increasing the drilling fluid density, which contradicts the conclusions drawn in a number of published wellbore stability case studies (Santarelli et al., 1992; McClellan et al., 1996; Edwards et al., 2004; Fontana et al., 2007).
Inhibition by cAMP of Ras-Dependent Activation of Raf (1993)

Activation of the Raf and extracellular signal-regulated kinases (ERKs) (or mitogen-activated protein kinases) are key events in mitogenic signalling, but little is known about interactions with other signaling pathways. Agents that raise levels of intracellular cyclic adenosine 3',5'-monophosphate (cAMP) blocked DNA synthesis and signal transduction in Rat1 cells exposed to epidermal growth factor (EGF) or lysophosphatidic acid. In the case of EGF, receptor tyrosine kinase activity and association with the signaling molecules Grb2 and Shc were unaffected by cAMP. Likewise, EGF-dependent accumulation of the guanosine 5'-triphosphate-bound form of Ras was unaffected. In contrast, activation of Raf-1 and ERK kinases was inhibited. Thus, cAMP appears to inhibit signal transmission from Ras by preventing Ras-dependent activation of Raf-1.
Study of injection bias in a simple hydrodynamic injection in microchip CE (2007)

The electrokinetically pinched method is the most commonly used mode for sample injection in microchip capillary electrophoresis (microCE) due to its simplicity and well-defined sample volume. However, the limited injection volume and the electrophoretic bias of the pinched injection may limit its universal usage to specific applications. Several hydrodynamic injection methods in microCE have been reported; however, almost all claimed that their methods are bias-free without considering the dispensing bias. To investigate the dispensing bias, a simple hydrodynamic injection was developed in single-T and double-T glass microchips. The sample flow was produced by hydrostatic pressure generated by the liquid level difference between the sample reservoir and the other reservoirs. The reproducibility of peak area and peak area ratio was improved to a significant extent using large-surface reservoirs for the buffer reservoir and the sample waste reservoir to reduce the Laplace pressure effect. Without a voltage applied on the sample solution, the voltage-related sample bias was eliminated. The dispensing bias was analyzed theoretically and studied experimentally. It was demonstrated that the dispensing bias existed and could be reduced significantly by appropriately setting up the voltage configuration and by controlling the appropriate liquid level difference.
The Mitsunobu Reaction: Origin, Mechanism, Improvements, and Applications (2007)

The Mitsunobu reaction is a widely used and versatile method for the dehydrative oxidation-reduction condensation of an acid/pronucleophile usually with a primary or secondary alcohol that requires the combination of a reducing phosphine reagent together with an oxidizing azo reagent. The utility of this reaction stems from the fact that it is generally highly stereoselective and occurs with inversion of the stereochemical configuration of the alcohol starting material. Furthermore, as carboxylic acids, phenols, imides, sulfonamides, and other compounds can be used as the acid/pronucleophile, this reaction is useful for the preparation of a wide variety of functional groups. This Focus Review of the Mitsunobu reaction summarizes its origins, the current understanding of its mechanism, and recent improvements and applications.
Determination of Peak Serum Levels and Immune Response to the Humanized Anti-Ganglioside Antibody-Interleukin-2 Immunocytokine (2003)

Tumor reactive monoclonal antibodies (mAb) have been developed and tested as anti-tumor therapy. Some mAb have shown efficacy and are now approved as clinical cancer therapy. The mechanism of action for the antitumor effect includes tumor cell destruction by effector cells with Fc receptors such as natural killer (NK) cells and macrophages. These cells recognize the mAb binding to the tumor cells and mediate antibody-dependent cellular cytotoxicity (ADCC). Enhanced ADCC is mediated by effector cells that have been activated by exposure to the cytokine IL-2 (1). Thus, in murine models, enhanced tumor destruction is produced when tumor bearing animals are treated with a combination of antitumor mAb and IL-2 (2). Clinical testing of mAb and IL-2 is underway.
Tyrosine Kinase Inhibitors of Vascular Endothelial Growth Factor Receptors in Clinical Trials: Current Status and Future Directions (2006)

Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of peptide growth factors and receptors are key regulators of this process. Agents directed either against VEGF or VEGF receptors (VEGFRs) have been developed. The tyrosine kinase inhibitors of VEGFRs are low-molecular-weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEG-FRs, resulting in blockade of intracellular signaling. Several of these agents are currently in different phases of clinical development. Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies, respectively. Positive results also have been reported with the combination of ZD6474 and chemotherapy in previously treated non-small cell lung cancer patients. For other agents, such as vatalanib, contrasting outcomes in metastatic colorectal cancer patients have been reported: the final results of these trials are expected in 2006. However, several key questions remain to be addressed, regarding the choice of an adequate dose or schedule, the presence of "off-target" effects, the safety of long-term administration, and the research of new clinical end points or methodological approaches for the optimal clinical development of these agents.
Efficiently Computed Lexical Chains as an Intermediate Representation for Automatic Text Summarization (2002)

While automatic text summarization is an area that has received a great deal of attention in recent research, the problem of efficiency in this task has not been frequently addressed. When the size and quantity of documents available on the Internet and from other sources are considered, the need for a highly efficient tool that produces usable summaries is clear. We present a linear-time algorithm for lexical chain computation. The algorithm makes lexical chains a computationally feasible candidate as an intermediate representation for automatic text summarization. A method for evaluating lexical chains as an intermediate step in summarization is also presented and carried out. Such an evaluation was heretofore not possible because of the computational complexity of previous lexical chains algorithms.
Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity (2021)

Although bespoke, sequence-specific proteases have the potential to advance biotechnology and medicine, generation of proteases with tailor-made cleavage specificities remains a major challenge. We developed a phage-assisted protease evolution system with simultaneous positive and negative selection and applied it to three botulinum neurotoxin (BoNT) light-chain proteases. We evolved BoNT/X protease into separate variants that preferentially cleave vesicle-associated membrane protein 4 (VAMP4) and Ykt6, evolved BoNT/F protease to selectively cleave the non-native substrate VAMP7, and evolved BoNT/E protease to cleave phosphatase and tensin homolog (PTEN) but not any natural BoNT protease substrate in neurons. The evolved proteases display large changes in specificity (218- to >11,000,000-fold) and can retain their ability to form holotoxins that self-deliver into primary neurons. These findings establish a versatile platform for reprogramming proteases to selectively cleave new targets of therapeutic interest.
Mechanical and acid neutralizing properties and bacteria inhibition of amorphous calcium phosphate dental nanocomposite (2011)

Dental composites do not hinder bacteria colonization and plaque formation. Caries at the restoration margins is a frequent reason for replacement of existing restorations, which accounts for 50 to 70% of all restorations. The objectives of this study were to examine the filler level effect on nanocomposite containing nanoparticles of amorphous calcium phosphate (NACP) and investigate the load-bearing and acid-neutralizing properties and bacteria inhibition. NACP with 116-nm particle size were synthesized via a spray-drying technique and incorporated into a resin. Flexural strength of nanocomposite with 10 to 30% NACP fillers matched the strength of a commercial hybrid composite (p > 0.1). Nanocomposite with 40% NACP matched the strength of a microfill composite, which was 2-fold that of a resin-modified glass ionomer. Nanocomposite with 40% NACP neutralized a lactic acid solution of pH 4 by rapidly increasing the pH to 5.69 in 10 min. In contrast, the commercial controls had pH staying at near 4. Using Streptoccocus mutans, an agar disk-diffusion test showed no inhibition zone for commercial controls. In contrast, the inhibition zone was (2.5 ± 0.7) mm for nanocomposite with 40% NACP. Crystal violet staining showed that S. mutans coverage on nanocomposite was 1/4 that on commercial composite. In conclusion, novel calcium-phosphate nanocomposite matched the mechanical properties of commercial composite and rapidly neutralized lactic acid of pH 4. The nanocomposite appeared to moderately reduce the S. mutans growth, and further study is needed to obtain strong antimicrobial properties. The new nanocomposite may have potential to reduce secondary caries and restoration fracture, two main challenges facing tooth cavity restorations.
Identification of the bile salt binding site on ipad from Shigella flexneri and the influence of ligand binding on IpaD structure (2011)

Type III secretion (TTS) is an essential virulence factor for Shigella flexneri, the causative agent of shigellosis. The Shigella TTS apparatus (TTSA) is an elegant nanomachine that is composed of a basal body, an external needle to deliver effectors into human cells, and a needle tip complex that controls secretion activation. IpaD is at the tip of the nascent TTSA needle where it controls the first step of TTS activation. The bile salt deoxycholate (DOC) binds to IpaD to induce recruitment of the translocator protein IpaB into the maturing tip complex. We recently used spectroscopic analyses to show that IpaD undergoes a structural rearrangement that accompanies binding to DOC. Here, we report a crystal structure of IpaD with DOC bound and test the importance of the residues that make up the DOC binding pocket on IpaD function. IpaD binds DOC at the interface between helices α3 and α7, with concomitant movement in the orientation of helix α7 relative to its position in unbound IpaD. When the IpaD residues involved in DOC binding are mutated, some are found to lead to altered invasion and secretion phenotypes. These findings suggest that adoption of a DOC bound structural state for IpaD primes the Shigella TTSA for contact with host cells. The data presented here and in the studies leading up to this work provide the foundation for developing a model of the first step in Shigella TTS activation.
On the Proper Interpretation of Indian Religion and Philosophy (1972)

This paper opposes Professor Potter’s idealistic interpretation of Indian philosophy. By contrast, I defend a Marxist, historical materialist interpretation of Indian philosophy.