gebhart/patrepeval huggingface dataset:
A Comparison of the Hydrochloride and Carbon Dioxide Salts of Lidocaine and Prilocaine in Epidural Analgesia (1965)

SUMMARY Lumbar epidural blockade has been used in a series of 659 patients to compare the analgesic properties of lidocaine and prilocaine. Solutions of both compounds were compared as hydrochloride salts in 2% and 3% concentration with and without adrenaline 1:200,000. Solutions of base, made soluble by equilibration with carbon dioxide at a pC0 2 of 700 mm Hg were also compared in concentrations of 1.75% for lidocaine and 1.71% for prilocaine. Comparisons were based on measurements of latency, spread of analgesia, intensity of motor blockade and duration of analgesia. The quality of blockade in all the test solutions was increased by the addition of 1:200,000 adrenaline. Prilocaine has a slow latency compared with lidocaine, but in plain solution its duration is longer than that of lidocaine. The 3% hydrochloride solutions have no practical advantage over die 2% solutions for epidural blockade. Analgesia resulting from the C0 2 ‐base solutions is superior in every respect to the blockade produced by equivalent concentrations of the hydrochloride salts.
A conserved motif in transmembrane helix 1 of diphtheria toxin mediates catalytic domain delivery to the cytosol (2005)

A 10-aa motif in transmembrane helix 1 of diphtheria toxin that is conserved in anthrax edema factor, anthrax lethal factor, and botulinum neurotoxin serotypes A, C, and D was identified by blast, clustal w, and meme computational analysis. Using the diphtheria toxin-related fusion protein toxin DAB(389)IL-2, we demonstrate that introduction of the L221E mutation into a highly conserved residue within this motif results in a nontoxic catalytic domain translocation deficient phenotype. To further probe the function of this motif in the process by which the catalytic domain is delivered from the lumen of early endosomes to the cytosol, we constructed a gene encoding a portion of diphtheria toxin transmembrane helix 1, T1, which carries the motif and is expressed from a CMV promoter. We then isolated stable transfectants of Hut102/6TG cells that express the T1 peptide, Hut102/6TG-T1. In contrast to the parental cell line, Hut102/6TG-T1 cells are ca. 10(4)-fold more resistant to the fusion protein toxin. This resistance is completely reversed by coexpression of small interfering RNA directed against the gene encoding the T1 peptide in Hut102/6TG-T1 cells. We further demonstrate by GST-DT140-271 pull-down experiments in the presence and absence of synthetic T1 peptides the specific binding of coatomer protein complex subunit beta to this region of the diphtheria toxin transmembrane domain.
Kinetic deuterium isotope effects on the N-demethylation of tertiary amides by cytochrome P-450. (1990)

Liver microsomal cytochrome P-450 readily N-dealkylates N,N-dimethylamides. N-Methyl-N-hydroxymethyl amides were isolated as intermediates and characterized by gas chromatography-mass spectrometry as their trimethylsilyl ethers. Intramolecular kinetic deuterium isotope effects measured for the enzymic N-demethylation of a series of 12 aromatic and aliphatic N-methyl-N-trideuteriomethyl amides, RCON(CH3)CD3, varied from 3.6 to 6.9 but were independent of both amide bond rotation rate and substrate oxidation potential. These values, which represent a lower limit to the intrinsic isotope effect (Dkintrinsic), are significantly larger than those observed for anodic N-demethylation and are consistent with a mechanism involving hydrogen atom abstraction. On the other hand, with N,N-dimethylbenzamide the intermolecular kinetic deuterium isotope effects on Vmax and Vmax/Km were found to be much smaller (1.23 and 1.75, respectively) indicating substantial suppression of the intrinsic isotope effect. Such suppression indicates the occurrence of a rate-limiting step other than the isotopically sensitive step together with a strong commitment to catalysis.
Reclassification of Bacteroides distasonis, Bacteroides goldsteinii and Bacteroides merdae as Parabacteroides distasonis gen. nov., comb. nov., Parabacteroides goldsteinii comb. nov. and Parabacteroides merdae comb. nov. (2006)

The characteristics of three Bacteroides species, Bacteroides distasonis, Bacteroides goldsteinii and Bacteroides merdae, were examined. 16S rRNA gene sequence analysis showed that B. distasonis, B. goldsteinii and B. merdae should not be classified as species within the genus Bacteroides. Although B. distasonis, B. goldsteinii and B. merdae were phylogenetically related to Tannerella forsythensis, the ratios of anteiso-C(15 : 0) to iso-C(15 : 0) in whole-cell methanolysates of the three species were different from that of T. forsythensis. In addition, whereas the major menaquinones of T. forsythensis were MK-10 and MK-11, the major menaquinones of B. distasonis, B. goldsteinii and B. merdae were MK-9 and MK-10. The three species were phenotypically similar to Bacteroides sensu stricto, but phylogenetically distinct. Furthermore, B. distasonis, B. goldsteinii and B. merdae could be differentiated from Bacteroides sensu stricto (predominant menaquinones: MK-10 and MK-11) by the menaquinone composition. This is an important chemotaxonomic characteristic of the three species. On the basis of these data, a novel genus, Parabacteroides gen. nov., is proposed for B. distasonis, B. goldsteinii and B. merdae, with three species, Parabacteroides distasonis gen. nov., comb. nov. (the type species), Parabacteroides goldsteinii comb. nov. and Parabacteroides merdae comb. nov. The type strains of P. distasonis, P. goldsteinii and P. merdae are JCM 5825(T) (=CCUG 4941(T)=DSM 20701(T)=ATCC 8503(T)), JCM 13446(T) (=CCUG 48944(T)) and JCM 9497(T) (=CCUG 38734(T)=ATCC 43184(T)), respectively.
Consistent resting-state networks across healthy subjects (2006)

Functional MRI (fMRI) can be applied to study the functional connectivity of the human brain. It has been suggested that fluctuations in the blood oxygenation level-dependent (BOLD) signal during rest reflect the neuronal baseline activity of the brain, representing the state of the human brain in the absence of goal-directed neuronal action and external input, and that these slow fluctuations correspond to functionally relevant resting-state networks. Several studies on resting fMRI have been conducted, reporting an apparent similarity between the identified patterns. The spatial consistency of these resting patterns, however, has not yet been evaluated and quantified. In this study, we apply a data analysis approach called tensor probabilistic independent component analysis to resting-state fMRI data to find coherencies that are consistent across subjects and sessions. We characterize and quantify the consistency of these effects by using a bootstrapping approach, and we estimate the BOLD amplitude modulation as well as the voxel-wise cross-subject variation. The analysis found 10 patterns with potential functional relevance, consisting of regions known to be involved in motor function, visual processing, executive functioning, auditory processing, memory, and the so-called default-mode network, each with BOLD signal changes up to 3%. In general, areas with a high mean percentage BOLD signal are consistent and show the least variation around the mean. These findings show that the baseline activity of the brain is consistent across subjects exhibiting significant temporal dynamics, with percentage BOLD signal change comparable with the signal changes found in task-related experiments.
The quest for the ultimate vacuum tube (2015)

In July, 1962, the Telstar 1 satellite took an enormous leap toward the globally connected world we now take for granted. It relayed from space, for the first time ever, live television images and telephone calls between continents: specifically, a ground station in Andover, Maine, and other stations in England and France. It accomplished this feat thanks to a microwave repeater that had at its heart a slight but powerful vacuum device known as a traveling-wave tube. The 30-centimeter-long, glasswalled electron tube was at the time the only device capable of boosting a broadband television signal with enough power to cross an ocean. Solid-state devices just weren't up to the task.
Cost-effectiveness of asenapine in the treatment of bipolar disorder in Canada (2014)

This economic evaluation demonstrates that asenapine is a cost-effective strategy compared to olanzapine in the treatment of BPD in Canada.
CORROSION COST AND PREVENTIVE STRATEGIES IN THE UNITED STATES (2002)

This report describes the annual total cost of metallic corrosion in the United States and preventive strategies for optimum corrosion management. In 1998, an amendment for a Cost of Corrosion study was included in the Transportation Equity Act for the 21st Century (TEA-21) and was approved by Congress. In the period from 1999 to 2001, CC Technologies conducted the research in a cooperative agreement with the Department of Transportation Federal Highway Administration (FHWA) and NACE International (The Corrosion Society). The total direct cost of corrosion is estimated at $276 billion per year, which is 3.1% of the 1998 U.S. gross domestic product (GDP). This cost was determined by analyzing 26 industrial sectors in which corrosion is known to exist and extrapolating the results for a nationwide estimate. The sectors were divided among five major categories: infrastructure, utilities, transportation, production and manufacturing, and government. The indirect cost of corrosion is conservatively estimated to be equal to the direct cost (i.e., total direct cost plus indirect cost is 6% of the GDP). Evidence of the large indirect corrosion costs is lost time, and thus lost productivity because of outages, delays, failures, and litigation. It was found that the sectors of drinking water and sewer systems ($36 billion), motor vehicles ($23.4 billion), and defense ($20 billion) have the largest direct corrosion impact. Within the total cost of corrosion, a total of $121 billion per year is spent on corrosion control methods and services. The current study showed that technological changes have provided many new ways to prevent corrosion and there has been improved use of available corrosion management techniques. However, better corrosion management can be achieved using preventive strategies in non-technical and technical areas. These preventive strategies include: (1) increase awareness of large corrosion costs and potential savings, (2) change the misconception that nothing can be done about corrosion, (3) change policies, regulations, standards, and management practices to increase corrosion cost-savings through sound corrosion management, (4) improve education and training of staff in recognition of corrosion control, (5) advance design practices for better corrosion management, (6) advance life prediction and performance assessment methods, and (7) advance corrosion technology through research, development, and implementation.
Photobiomodulation Directly Benefits Primary Neurons Functionally Inactivated by Toxins (2004)

Far red and near infrared (NIR) light promotes wound healing, but the mechanism is poorly understood. Our previous studies using 670 nm light-emitting diode (LED) arrays suggest that cytochrome c oxidase, a photoacceptor in the NIR range, plays an important role in therapeutic photobiomodulation. If this is true, then an irreversible inhibitor of cytochrome c oxidase, potassium cyanide (KCN), should compete with LED and reduce its beneficial effects. This hypothesis was tested on primary cultured neurons. LED treatment partially restored enzyme activity blocked by 10-100 microm KCN. It significantly reduced neuronal cell death induced by 300 microm KCN from 83.6 to 43.5%. However, at 1-100 mm KCN, the protective effects of LED decreased, and neuronal deaths increased. LED significantly restored neuronal ATP content only at 10 microm KCN but not at higher concentrations of KCN tested. Pretreatment with LED enhanced efficacy of LED during exposure to 10 or 100 microm KCN but did not restore enzyme activity to control levels. In contrast, LED was able to completely reverse the detrimental effect of tetrodotoxin, which only indirectly down-regulated enzyme levels. Among the wavelengths tested (670, 728, 770, 830, and 880 nm), the most effective ones (830 nm, 670 nm) paralleled the NIR absorption spectrum of oxidized cytochrome c oxidase, whereas the least effective wavelength, 728 nm, did not. The results are consistent with our hypothesis that the mechanism of photobiomodulation involves the up-regulation of cytochrome c oxidase, leading to increased energy metabolism in neurons functionally inactivated by toxins.
Resistance to herbicides caused by single amino acid mutations in acetyl‐CoA carboxylase in resistant populations of grassy weeds (2013)

Eleven spontaneous mutations of acetyl-CoA carboxylase have been identified in many herbicide-resistant populations of 42 species of grassy weeds, hampering application of aryloxyphenoxypropionate, cyclohexadione and phenylpyrazoline herbicides in agriculture. IC(50) shifts (resistance indices) caused by herbicide-resistant mutations were determined using a recombinant yeast system that allows comparison of the effects of single amino acid mutations in the same biochemical background, avoiding the complexity inherent in the in planta experiments. The effect of six mutations on the sensitivity of acetyl-CoA carboxylase to nine herbicides representing the three chemical classes was studied. A combination of partially overlapping binding sites of the three classes of herbicides and the structure of their variable parts explains cross-resistance among and between the three classes of inhibitors, as well as differences in their specificity. Some degree of resistance was detected for 51 of 54 herbicide/mutation combinations. Introduction of new herbicides targeting acetyl-CoA carboxylase will depend on their ability to overcome the high degree of cross-resistance already existing in weed populations.
Addiction to Elevated Insulin-like Growth Factor I Receptor and Initial Modulation of the AKT Pathway Define the Responsiveness of Rhabdomyosarcoma to the Targeting Antibody (2008)

Insulin-like growth factor I receptor (IGF-IR) and its ligands are overexpressed by tumors, mediating proliferation and protecting against stress-induced apoptosis. Accordingly, there has been a considerable amount of interest in developing therapeutic agents against IGF-IR. IGF-IR is believed to be ubiquitously expressed without detectable mutation or amplification in cancer. We explored the determinants of cellular response to a humanized anti-IGF-IR antibody. Our results showed a large variation in IGF-IR levels in rhabdomyosarcoma tumor specimens that were comparable with those in rhabdomyosarcoma cell lines. In vitro analysis revealed a direct and very significant correlation between elevated IGF-IR levels and antiproliferative effects of the antibody and defined a receptor number that would predict sensitivity. Our data further suggested a strong dependence on IGF-IR for AKT signaling in cells with elevated IGF-IR. The sensitivity of the high IGF-IR-expressing cells was blocked with a constitutively active AKT. The extracellular signal-regulated kinase pathway was not affected by the antibody. In vivo studies showed that anti-IGF-IR had single-agent antitumor activity; furthermore, predictions of responses based on IGF-IR levels were accurate. In vivo biomarker analysis suggested that h7C10 down-regulated both IGF-IR and p-AKT initially, concordant with antitumor activity. Subsequent progression of tumors was associated with reactivation of p-AKT despite sustained suppression of IGF-IR. These results identified the first predictive biomarker for anti-IGF-IR therapies in cancer.
Type-II Superconducting Strip in Perpendicular Magnetic Field (1993)

The current density and local magnetic field are calculated analytically for a strip of a type-II superconductor in perpendicular magnetic field Ha for constant critical current density. The penetrating flux front has vertical slope and the initial penetration depth, magnetization change and hysteretic losses are ∼ Ha2, ∼ Ha3 and ∼ Ha4, respectively. The analytical results differ from the widely used Bean model and explain numerous experiments in a natural way without the assumption of a surface barrier.
Structures of the extracellular regions of the group II/III metabotropic glutamate receptors (2007)

Metabotropic glutamate receptors play major roles in the activation of excitatory synapses in the central nerve system. We determined the crystal structure of the entire extracellular region of the group II receptor and that of the ligand-binding region of the group III receptor. A comparison among groups I, II, and III provides the structural basis that could account for the discrimination of group-specific agonists. Furthermore, the structure of group II includes the cysteine-rich domain, which is tightly linked to the ligand-binding domain by a disulfide bridge, suggesting a potential role in transmitting a ligand-induced conformational change into the downstream transmembrane region. The structure also reveals the lateral interaction between the two cysteine-rich domains, which could stimulate clustering of the dimeric receptors on the cell surface. We propose a general activation mechanism of the dimeric receptor coupled with both ligand-binding and interprotomer rearrangements.
Novel genetically-humanized mouse model established to evaluate efficacy of therapeutic agents to human interleukin-6 receptor (2013)

For clinical trials of therapeutic monoclonal antibodies (mAbs) to be successful, their efficacy needs to be adequately evaluated in preclinical experiments. However, in many cases it is difficult to evaluate the candidate mAbs using animal disease models because of lower cross-reactivity to the orthologous target molecules. In this study we have established a novel humanized Castleman's disease mouse model, in which the endogenous interleukin-6 receptor gene is successfully replaced by human IL6R, and human IL6 is overexpressed. We have also demonstrated the therapeutic effects of an antibody that neutralizes human IL6R, tocilizumab, on the symptoms in this mouse model. Plasma levels of human soluble IL6R and human IL6 were elevated after 4-week treatment of tocilizumab in this mouse model similarly to the result previously reported in patients treated with tocilizumab. Our mouse model provides us with a novel means of evaluating the in vivo efficacy of human IL6R-specific therapeutic agents.
Adjuvant Activity of the Heat-Labile Enterotoxin from Enterotoxigenic Escherichia coli for Oral Administration of Inactivated Influenza Virus Vaccine (1997)

Alternative strategies for vaccination against influenza that elicit both systemic antibody and mucosal IgA responses are needed to improve the efficacy in protection against infection. This study demonstrated that oral delivery of inactivated influenza vaccine with the heat-labile enterotoxin (LT) from enterotoxigenic Escherichia coli elicited the spectrum of humoral and cell-mediated responses in BALB/c mice critical for the protection and recovery from influenza virus infection. Coadministration of LT with oral influenza vaccine increased antiviral serum IgG and mucosal IgA responses compared with administration of oral influenza vaccine alone. Serum hemagglutination-inhibition and neutralizing antibodies were also augmented by LT. The adjuvant potentiated protection from infection with influenza A H3N2 viruses in mouse lower and upper respiratory tracts, enabling the use of lower doses of oral vaccine. Coadministration of LT with oral inactivated influenza vaccine induced influenza virus-specific proliferative T cells, interleukin-2 production, and major histocompatibility complex class I-restricted cytotoxic T cells.
GLP-1 Receptor Antagonist Exendin-(9-39) Elevates Fasting Blood Glucose Levels in Congenital Hyperinsulinism Owing to Inactivating Mutations in the ATP-Sensitive K+ Channel (2012)

Infants with congenital hyperinsulinism owing to inactivating mutations in the K(ATP) channel (K(ATP)HI) who are unresponsive to medical therapy will require pancreatectomy to control the hypoglycemia. In preclinical studies, we showed that the GLP-1 receptor antagonist exendin-(9-39) suppresses insulin secretion and corrects fasting hypoglycemia in SUR-1(-/-) mice. The aim of this study was to examine the effects of exendin-(9-39) on fasting blood glucose in subjects with K(ATP)HI. This was a randomized, open-label, two-period crossover pilot clinical study. Nine subjects with K(ATP)HI received either exendin-(9-39) or vehicle on two different days. The primary outcome was blood glucose; secondary outcomes were insulin, glucagon, and GLP-1. In all subjects, mean nadir blood glucose and glucose area under the curve were significantly increased by exendin-(9-39). Insulin-to-glucose ratios were significantly lower during exendin-(9-39) infusion compared with vehicle. Fasting glucagon and intact GLP-1 were not affected by treatment. In addition, exendin-(9-39) significantly inhibited amino acid-stimulated insulin secretion in pancreatic islets isolated from neonates with K(ATP)HI. Our findings have two important implications: 1) GLP-1 and its receptor play a role in the regulation of fasting glycemia in K(ATP)HI; and 2) the GLP-1 receptor may be a therapeutic target for the treatment of children with K(ATP)HI.
11β-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress (1997)

Glucocorticoid hormones, acting via nuclear receptors, regulate many metabolic processes, including hepatic gluconeogenesis. It recently has been recognized that intracellular glucocorticoid concentrations are determined not only by plasma hormone levels, but also by intracellular 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), which interconvert active corticosterone (cortisol in humans) and inert 11-dehydrocorticosterone (cortisone in humans). 11beta-HSD type 2, a dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data suggest the type 1 isozyme (11beta-HSD-1) may function as an 11beta-reductase, regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. To examine the importance of this enzyme isoform in vivo, mice were produced with targeted disruption of the 11beta-HSD-1 gene. These mice were unable to convert inert 11-dehydrocorticosterone to corticosterone in vivo. Despite compensatory adrenal hyperplasia and increased adrenal secretion of corticosterone, on starvation homozygous mutants had attenuated activation of the key hepatic gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, presumably, because of relative intrahepatic glucocorticoid deficiency. The 11beta-HSD-1 -/- mice were found to resist hyperglycamia provoked by obesity or stress. Attenuation of hepatic 11beta-HSD-1 may provide a novel approach to the regulation of gluconeogenesis.