gebhart/patrepeval huggingface dataset:
General Anesthetics and Molecular Mechanisms of Unconsciousness (2008)

General anesthetic agents are unique in clinical medicine, because they are the only drugs used to produce unconsciousness as a therapeutic goal. In contrast to older hypotheses that assumed all general anesthetics produce their central nervous system effects through a common mechanism, we outline evidence that general anesthesia represents a number of distinct pharmacological effects that are likely mediated by different neural circuits, and perhaps via different molecular targets. Within the context of this neurobiological framework, we review recent molecular pharmacological and transgenic animal studies. These studies reveal that different groups of general anesthetics, which can be discerned based on their clinical features, produce unconsciousness via distinct molecular targets and therefore via distinct mechanisms. We further postulate that different types of general anesthetics selectively disrupt different critical steps (perhaps in different neuronal circuits) in the processing of sensory information and memory that results in consciousness.
Human ATP-binding cassette transporter ABCC10: expression profile and p53-dependent upregulation. (2004)

Human ATP-binding cassette (ABC) transporter genes are classified into seven sub-families, where "C" subfamily comprises a total of 13 gene members. The ABCC10 cDNA was cloned in the human full-length cDNA project at the Kazusa DNA Research Institute. However, current information is limited regarding its physiological function and gene expression. In the present study, we have investigated the expression of the ABCC10 gene to gain insight into its biological nature. By quantitative PCR, ABCC10 gene expression is demonstrated to be highest in pancreas among the adult and fetal tissues and tumors presently tested. Decreased expression was observed when resting T- and B-cells were activated. Furthermore, when we examined its expression under apoptotic conditions, we found that ABCC10 mRNA levels remarkably increased in doxorubicin-treated MCF7 cells, whereas its up-regulation was suppressed in p53-dominant-negative MCF7 cells. These results suggest that expression of the ABCC10 gene is regulated in a p53-dependent manner during DNA-damage-related apoptosis.
A Resonant Global Clock Distribution for the Cell Broadband Engine Processor (2009)

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> Resonant clock distributions have the potential to save power by recycling energy from cycle-to-cycle while at the same time improving performance by reducing the clock distribution latency and filtering out non-periodic noise. While these features have been successfully demonstrated in several small-scale experiments, there remained a number of concerns about whether these techniques would scale to a product application. By modifying the Cell Broadband Engine Processor to incorporate a large resonant global clock network, power savings with full functionality is demonstrated over a 20% range in clock frequencies, and a 6–8 Watt power savings at 4 GHz. This was achieved by changing one wiring level and adding an additional thick copper level to create inductors and capacitors. </para>
The World Its Parish: Wesleyan Theology in the Postmodern Global Village (2004)

A number of leg ulcer specialist/tissue viability specialists from across the UK were invited to evaluate PICO (Smith and Nephew, Hull) as a treatment for venous leg ulcers also in conjunction with a variety of compression bandages and garments. Patients across 5 sites had PICO applied in conjunction with compression therapy. This group of treating clinicians were then asked to give feedback on the outcome of the patients on whom they had used the new device. All feedback was recorded at a meeting and this was used to create a guideline for use.
Delivery Platform for Hydrophobic Drugs:  Prodrug Approach Combined with Self-Assembled Multilayers (2005)

We report the design of a platform for the delivery of hydrophobic drugs via a macromolecular prodrug approach combined with LbL-assembled polyelectrolyte multilayers. A hyaluronan ester prodrug of the chemotherapeutic drug paclitaxel has been synthesized. Conjugation of the drug to hyaluronan through a labile succinate ester did not inhibit its activity. Using quartz crystal microbalance, atomic force microscopy, and UV spectroscopy, we have shown that the presence of the hydrophobic paclitaxel moieties does not prohibit the layer-by-layer construction of the multilayers. Release of the drug from the paclitaxel-loaded multilayers upon hydrolysis of the ester linkage resulted in a drastic cell death. Application of this delivery platform to substrates such as colloids, biomedical implants, or vascular tissues may lead to new therapeutic strategies.
Computational epigenetics (2007)

Epigenetic research aims to understand heritable gene regulation that is not directly encoded in the DNA sequence. Epigenetic mechanisms such as DNA methylation and histone modifications modulate the packaging of the DNA in the nucleus and thereby influence gene expression. Patterns of epigenetic information are faithfully propagated over multiple cell divisions, which makes epigenetic regulation a key mechanism for cellular differentiation and cell fate decisions. In addition, incomplete erasure of epigenetic information can lead to complex patterns of non-Mendelian inheritance. Stochastic and environment-induced epigenetic defects are known to play a major role in cancer and ageing, and they may also contribute to mental disorders and autoimmune diseases. Recent technical advances such as ChIP-on-chip and ChIP-seq have started to convert epigenetic research into a high-throughput endeavor, to which bioinformatics is expected to make significant contributions. Here, we review pioneering computational studies that have contributed to epigenetic research. In addition, we give a brief introduction into epigenetics-targeted at bioinformaticians who are new to the field-and we outline future challenges in computational epigenetics.
Initial studies of monoclonal antibody PAM4 targeting to xenografted orthotopic pancreatic cancer. (1995)

To resemble the clinical presentation of pancreatic cancer in an animal model more closely, we developed an orthotopic xenograft of CaPan-1 human pancreatic cancer in athymic nude mice. Within 3 weeks after implantation into the body and head of the pancreas, animals had palpable tumors. By 8 weeks, metastases to the liver and spleen were observed, and at 10-14 weeks, ascites formation, with and without seeding of the diaphragm, and jaundice were evident. Thus, this tumor model exhibited many of the most common features of human pancreatic cancer. Radiolabeled monoclonal antibody PAM4 showed specific localization of the primary orthotopic and metastatic tumors. On day 3, PAM4 accumulation within the primary tumor (0.5 g) was 11.3 +/- 5.1% injected dose/g with a localization index of 11.3 +/- 4.0. The estimated tumor:blood radiation dose ratio for PAM4 was 4:1, whereas a nonspecific antibody (Ag8) would provide only 40% of the blood dose to the tumor. Based on these observations, animals bearing 4-week-old orthotopic tumors (estimated volume, 0.25 cm3) were administered either 131I-labeled PAM4, 350 microCi, or nonspecific Ag8, 350 microCi, and compared with an untreated control group. Radiolabeled PAM4 provided a significant (P < 0.001) increase in survival time with less morbidity compared with the untreated control group, whereas nonspecific Ag8 was not significantly different from the control group. These studies provide a rationale for initiating a Phase I clinical study for detection and therapy of pancreatic cancer with PAM4.
The Pneumococcal Serotype 15C Capsule Is Partially O-Acetylated and Allows for Limited Evasion of 23-Valent Pneumococcal Polysaccharide Vaccine-Elicited Anti-Serotype 15B Antibodies (2017)

As a species, <i>Streptococcus pneumoniae</i> (the pneumococcus) utilizes a diverse array of capsular polysaccharides to evade the host. In contrast to large variations in sugar composition and linkage formation, O-acetylation is a subtle capsular modification that nonetheless has a large impact on capsular shielding and recognition of the capsule by vaccine-elicited antibodies. Serotype 15B, which is included in the 23-valent pneumococcal polysaccharide vaccine (PPV23), carries the putative O-acetyltransferase gene <i>wciZ</i> The coding sequence of <i>wciZ</i> contains eight consecutive TA repeats [(TA)<sub>8</sub>]. Replication slippage is thought to result in the addition or loss of TA repeats, subsequently causing frameshift and truncation of WciZ to yield a nonacetylated serotype, 15C. Using sensitive serological tools, we show that serotype 15C isolates whose <i>wciZ</i> contains seven or nine TA repeats retain partial O-acetylation, while serotype 15C isolates whose <i>wciZ</i> contains six TA repeats have barely detectable O-acetylation. We confirmed by inhibition enzyme-linked immunosorbent assay that (TA)<sub>7</sub> serotype 15C is ∼0.1% as acetylated as serotype 15B, while serotype 15X is nonacetylated. To eliminate the impact of genetic background, we created isogenic serotype 15B, (TA)<sub>7</sub> serotype 15C, and 15BΔ<i>wciZ</i> (15X) strains and found that reduction or absence of WciZ-mediated O-acetylation did not affect capsular shielding from phagocytes, biofilm formation, adhesion to nasopharyngeal cells, desiccation tolerance, or murine colonization. Sera from PPV23-immunized persons opsonized serotype 15B significantly but only slightly better than serotypes 15C and 15X; thus, PPV23 may not result in expansion of serotype 15C.
Automated ECG rhythm analysis using fuzzy reasoning (2002)

Presents a fuzzy reasoning approach for ECG beat and rhythm detection and classification. Linguistic variables are used to represent beat features and fuzzy conditional statements perform reasoning. Five beat types and more than 20 arrhythmias were considered. The method performed well when evaluated with the MIT-BIH Arrhythmia Database. It conveniently summarizes and makes use of medical knowledge and diagnostic rules, and has promise for more complicated clinical applications such as multi-parameter intelligent patient monitoring systems.
Sensitive receptor-specified enzyme-linked immunosorbent assay for Escherichia coli verocytotoxin (1989)

The specific identification of verocytotoxin (VT)-producing Escherichia coli (VTEC) requires the detection of VTs in bacterial culture filtrates or the detection of genes encoding these toxins in bacterial cells by specific DNA probes. The standard method for detecting these toxins involves a time-consuming, labor-intensive, and expensive cytotoxicity assay. We have developed a specific, highly sensitive receptor-specified enzyme-linked immunosorbent assay (RELISA) to detect VT1, one of at least two VTs implicated in human disease. The assay is based on the affinity of VT1 for the glycolipid globotriosyl ceramide (Gb3). Gb3 was de-N-acylated to yield lyso-Gb3, which is more polar but retains VT1 binding. Lyso-Gb3 was used to sensitize microdilution plates to bind VT1 for subsequent immunodetection. This RELISA was used to detect VT1 in the culture supernatant of a variety of bacteria of known VT status. The assay was compared with the highly sensitive cell cytotoxicity assay for their abilities to detect VT. The RELISA was as sensitive as the cytotoxicity assay and, in a blind study, 100% specific. This assay will provide a quick, specific, efficient adjunct to the diagnosis and epidemiological study of VTEC infections and their relationship to human disease.
Lectins and traffic in the secretory pathway (2000)

Evidence is accumulating that intracellular animal lectins play important roles in quality control and glycoprotein sorting along the secretory pathway. Calnexin and calreticulin in conjunction with associated chaperones promote correct folding and oligomerization of many glycoproteins in the endoplasmic reticulum (ER). The mannose lectin ERGIC-53 operates as a cargo receptor in transport of glycoproteins from ER to Golgi and the homologous lectin VIP36 may operate in quality control of glycosylation in the Golgi. Exit from the Golgi of lysosomal hydrolases to endosomes requires mannose 6-phosphate receptors and exit to the apical plasma membrane may also involve traffic lectins. Here we discuss the features of these lectins and their role in glycoprotein traffic in the secretory pathway.
Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. (1996)

Reversible airway hyperreactivity underlies the pathophysiology of asthma, yet the precise mediators of the response remain unclear. Human studies have correlated aberrant activation of T helper (Th) 2-like effector systems in the airways with disease. A murine model of airway hyperreactivity in response to acetylcholine was established using mice immunized with ovalbumin and challenged with aerosolized antigen. No airway hyperractivity occurred in severe combined immunodeficient mice. Identically immunized BALB/c mice developed an influx of cells, with a predominance of eosinophils and CD4+ T cells, into the lungs and bronchoalveolar lavage fluid at the time that substantial changes in airway pressure and resistance were quantitated. Challenged animals developed marked increases in Th2 cytokine production, eosinophil influx, and serum immunoglobulin E levels. Neutralization of interleukin (IL) 4 using monoclonal antibodies administered during the period of systemic immunization abrogated airway hyperractivity but had little effect on the influx of eosinophils. Administration of anti-IL-4 only during the period of the aerosol challenge did not affect the subsequent response to acetylcholine. Finally, administration of anti-IL-5 antibodies at levels that suppressed eosinophils to < 1% of recruited cells had no effect on the subsequent airway responses. BALB/c mice had significantly greater airway responses than C57BL/6 mice, consistent with enhanced IL-4 responses to antigen in BALB/c mice. Taken together, these data implicate IL-4 generated during the period of lymphocyte priming with antigen in establishing the cascade of responses required to generate airway hyperractivity to inhaled antigen. No role for IL-5 or eosinophils could be demonstrated.
Hydrazines et hydrazones hétérocycliques. IV. Synthèses de dérivés de l'hydrazine dans la série des imidazo[4,5-d] pyridazinones-4 (1983)

We report the syntheses of 5-alkyl or 5-aryl-3,5-dihydro[4,5-d]imidazo-4-pyridazinones (or the 1,5-dihydro derivatives) from the corresponding diaminopyridazinones. The methylation of 5-alkyl or 5-aryl-2-mercapto-3,5 (or 1,5)-dihydro [4,5-d]imidazo-4-pyridazinones leads to mixtures of 5-alkyl or 5-aryl-1 methyl-2-methylthio-3,5 (1,5)-dihydro[4,5-d]imidazo-4-pyridazinones and 5-alkyl or 5-aryl-3-methyl-2-methylthio-3,5 (or 1,5)-dihydro[4,5-d]imidazo-4-pyridazinones whose structures have been established by the Overhauser effect. These [4,5-d]imidazo-4-pyridazinones are used for the syntheses of hydrazines and hydrozones. The mass spectra of several key intermediates are presented and discussed. [Journal translation]
Homodimeric Tacrine Congeners as Acetylcholinesterase Inhibitors (2002)

In the search for highly selective and potent derivatives of tacrine (1a), a number of homodimeric tacrine congeners were synthesized and conducted for their effects on rat acetylcholinesterase (AChE) and human butyrylcholinesterase (BChE) inhibitions. Heptylene-linked bis-(6-chloro)tacrine (3h) was found up to 3000- and 3-fold more potent in inhibiting rat AChE than tacrine and the unsubstituted bis-tacrine 3b, respectively. Changes in the size of the carbocyclic ring of the dimeric tacrine reduced both the selectivity and the potency of AChE inhibition as compared to 3b. Inserting an aza into the tacrine nucleus as the desired isosteres 3j-m resulted in moderate potency but tended to be detrimental to selectivity. The pronounced enhancement of AChE inhibition potency and AChE/BChE selectivity was achieved with incorporation of a halogen at the 6-position of homodimeric tacrines. The assay results of 3a-m also provided evidence that the 7-methylene tether tended to be optimal to AChE inhibition potency.
Regulation of Interleukin-2 Gene Enhancer Activity by the T Cell Accessory Molecule CD28 (1991)

The mechanism by which cell surface molecules regulate T cell production of lymphokines is poorly understood. Production of interleukin-2 (IL-2) can be regulated by signal transduction pathways distinct from those induced by the T cell antigen receptor. Stimulation of CD28, a molecule expressed on most human T cells, induced the formation of a protein complex that bound to a site on the IL-2 gene distinct from previously described binding sites and increased IL-2 enhancer activity fivefold. The CD28-responsive complex bound to the IL-2 gene between -164 and -154 base pairs from the transcription start site. The sequence of this element is similar to regions conserved in the 5' flanking regions of several other lymphokine genes.
Chemical synthesis of DNA and DNA analogs (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleChemical synthesis of DNA and DNA analogsMarvin H. CaruthersCite this: Acc. Chem. Res. 1991, 24, 9, 278–284Publication Date (Print):September 1, 1991Publication History Published online1 May 2002Published inissue 1 September 1991https://pubs.acs.org/doi/10.1021/ar00009a005https://doi.org/10.1021/ar00009a005research-articleACS PublicationsRequest reuse permissionsArticle Views2259Altmetric-Citations228LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
A high-performance liquid chromatographic method for the determination of tocopherol in plasma and cellular elements of the blood. (1979)

A rapid sensitive, and reproducible procedure is described for the analysis of alpha-tocopherol in blood cells and plasma using high-performance liquid chromatography and fluorometric detection. The cardinal feature for the increased sensitivity of this high-performance liquid chromatographic procedure is that the fluorometric analysis was carried out at a short excitation wavelength (205 nm) which increased the sensitivity of 20-fold over the usual excitation wavelength of 295 nm. Tocopherol levels can be measured in as little as 50 microliters of plasma and 200 microliters of erythrocytes. The tocopherol contentof plasma, red blood cells, platelets, polymorphonuclear leukocytes, and lymphocytes of normal subjects and subjects ingesting additional quantitites of vitamin E are reported. The values for the white cells are approximately 30 times higher than those of the red blood cells (polymorphonuclear leukocytes 4.47 +/- 0.62 micrograms/10(9), lymphocytes 3.89 +/- 0.85 micrograms/10(9), and erythrocytes 1.40 +/- 0.14 micrograms/10(10) cells). The tocopherol contents of the plasma and all the cellular elements of the blood were increased by oral feeding with vitamin E.
Cache partitioning strategies for 3-D stacked vector processors (2010)

An on-chip cache memory for vector processors, named vector cache, has been proposed to realize a high sustained memory bandwidth, which is balanced with the high computational performance of future vector processors. In our previous research, from the viewpoint of architectural design, it is clearly shown that the 3D die-stacking technology can increase the capacity of the vector cache and thereby the performance of vector processors. However, detailed design of vector caches with the 3D die-stacking technology has not been discussed well yet. Therefore it is still unclear how much the vector cache can benefit from the 3D die-stacking technology in terms of cost, latency, and energy consumption. In this paper, the vector caches are designed in detail so as to exploit the advantages of the 3D die-stacking technologies, such as reductions in long wires and energy consumption. In the cache design, this paper examines two strategies to partition the vector caches into some blocks and to place them onto multiple layers. One cache partitioning strategy places more emphasis on the reduction in the number of long wires. The other strategy reduces the number of through-silicon vias (TSVs). This paper evaluates latency, energy consumption, and the number of TSVs used in each cache partitioning strategy. This paper also discusses the 3D cache configuration suitable for vector processors.
Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections (2016)

Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.
Efficient Convergent Synthesis of Bi-, Tri-, and Tetra-antennary Complex Type N-Glycans and Their HIV-1 Antigenicity (2013)

The structural diversity of glycoproteins often comes from post-translational glycosylation with heterogeneous N-glycans. Understanding the complexity of glycans related to various biochemical processes demands a well-defined synthetic sugar library. We report herein a unified convergent strategy for the rapid production of bi-, tri-, and tetra-antennary complex type N-glycans with and without terminal N-acetylneuraminic acid residues connected via the α-2,6 or α-2,3 linkages. Moreover, using sialyltransferases to install sialic acid can minimize synthetic steps through the use of shared intermediates to simplify the complicated procedures associated with conventional sialic acid chemistry. Furthermore, these synthetic complex oligosaccharides were compiled to create a glycan array for the profiling of HIV-1 broadly neutralizing antibodies PG9 and PG16 that were isolated from HIV infected donors. From the study of antibody PG16, we identified potential natural and unnatural glycan ligands, which may facilitate the design of carbohydrate-based immunogens and hasten the HIV vaccine development.