gebhart/patrepeval huggingface dataset:
Protein Kinase C-Independent Activation of the Epstein-Barr Virus Lytic Cycle (2002)

The protein kinase C (PKC) pathway has been considered to be essential for activation of latent Epstein-Barr virus (EBV) into the lytic cycle. The phorbol ester tetradecanoyl phorbol acetate (TPA), a PKC agonist, is one of the best understood activators of EBV lytic replication. Zp, the promoter of the EBV immediate-early gene BZLF1, whose product, ZEBRA, drives the lytic cycle, contains several phorbol ester response elements. We investigated the role of the PKC pathway in lytic cycle activation in prototype cell lines that differed dramatically in their response to inducing agents. We determined whether PKC was involved in lytic cycle induction by histone deacetylase (HDAC) inhibitors. Consistent with prevailing views, B95-8 cells were activated into the lytic cycle by the phorbol ester TPA, via a PKC-dependent mechanism. B95-8 was not inducible by HDAC inhibitors such as n-butyrate and trichostatin A (TSA). Bisindolylmaleimide I, a selective PKC inhibitor, blocked lytic cycle activation in B95-8 cells in response to TPA. In marked contrast, in HH514-16 cells, the immediate-early promoters Zp and Rp were simultaneously activated by the HDAC inhibitors; TPA by itself failed to activate lytic gene expression. Inhibition of PKC activity by bisindolylmaleimide I did not block lytic cycle activation in HH514-16 cells by n-butyrate or TSA. In an extensive exploration of the mechanism underlying these different responses we found that the variable role of the PKC pathway in the two cell lines could not be accounted for by significant polymorphisms in the promoters of the immediate-early genes, by differences in the start sites of immediate-early gene transcription, or by differences in the nucleosomal organization of EBV DNA in the region of Zp or Rp. While B95-8 cells contained more total PKC activity than did HH514-16 cells in an in vitro assay, another EBV-transformed marmoset lymphoblastoid cell line, FF41, in which the lytic cycle was not inducible by TPA, contained comparably high levels of PKC activity. Moreover, two marmoset lymphoblastoid cells lines in which the lytic cycle could not be triggered by TPA maintained the same profile of EBV latency proteins as B95-8 cells. Thus, the profile of EBV latency proteins did not account for susceptibility to induction by PKC agonists. PKC activation is neither obligatory nor sufficient for the switch between latency and lytic cycle gene expression of EBV in many cell backgrounds. Lytic cycle induction by HDAC inhibitors proceeds by a PKC-independent mechanism.
Electrochemical Nitric Oxide Sensors for Biological Samples – Principle, Selected Examples and Applications (2003)

Abstract The discoveries made in the 1980s that NO could be synthesized by mammalian cells and could act as physiological messenger and cytotoxic agent had elevated the importance of its detection. The numerous properties of NO, that enable it to carry out its diverse functions, also present considerable problems when attempting its detection and quantification in biological systems. Indeed, its total free concentration in physiological conditions has been established to be in nanomolar range. Thus, detection of nitric oxide remains a challenge, pointing out the difficult dual requirements for specificity and sensitivity. Exception made for the electrochemical techniques, most of the approaches (namely UV‐visible spectroscopy, fluorescence, electron paramagnetic resonance spectroscopy) use indirect methods for estimating endogenous NO, relying on measurements of secondary species such as nitrite and nitrate or NO‐adducts. They also suffer from allowing only ex situ measurements. So, the only strategies that allow a direct and in vivo detection of NO are those based on the use of ultramicroelectrodes. The reality is that surface electrode modification is needed to make the ultramicroelectrode material selective for NO. Therefore, the design of modified electrode surfaces using organized layers is very attractive and provides the ideal strategy. This review addresses a global description of the various approaches that have involved chemically modified microelectrodes specially designed for the electrochemical detection of NO in biological media. Selected significant examples of applications in biological tissues are also reported in order to highlight the importance of this approach in having new insights into the modulatory role of NO in physiology and pathophysiology.
Oxygen Gas–Filled Microparticles Provide Intravenous Oxygen Delivery (2012)

We have developed an injectable foam suspension containing self-assembling, lipid-based microparticles encapsulating a core of pure oxygen gas for intravenous injection. Prototype suspensions were manufactured to contain between 50 and 90 ml of oxygen gas per deciliter of suspension. Particle size was polydisperse, with a mean particle diameter between 2 and 4 μm. When mixed with human blood ex vivo, oxygen transfer from 70 volume % microparticles was complete within 4 s. When the microparticles were infused by intravenous injection into hypoxemic rabbits, arterial saturations increased within seconds to near-normal levels; this was followed by a decrease in oxygen tensions after stopping the infusions. The particles were also infused into rabbits undergoing 15 min of complete tracheal occlusion. Oxygen microparticles significantly decreased the degree of hypoxemia in these rabbits, and the incidence of cardiac arrest and organ injury was reduced compared to controls. The ability to administer oxygen and other gases directly to the bloodstream may represent a technique for short-term rescue of profoundly hypoxemic patients, to selectively augment oxygen delivery to at-risk organs, or for novel diagnostic techniques. Furthermore, the ability to titrate gas infusions rapidly may minimize oxygen-related toxicity.
Transition flight control for Canard Rotor/Wing rotorcraft (2011)

Canard Rotor/Wing (CRW) Unmanned Aerial Vehicle (UAV) combines advantages of a helicopter for taking-off and hover, and a fixed-wing aircraft for high speed cruise. A key technology involved is control system design for transition flight. This paper describes flight characteristic of CRW UAV with achieving transition flight from helicopter mode to fixed-wing mode. Dynamic model is built and analyzed. Control strategy is proposed for three flight modes, including helicopter mode, conversion mode and fixed-wing mode. Then, flight control law is designed by modified nonlinear dynamic inversion technique. In addition, we succeed to allocate redundant control inputs for the CRW with generalized multiple control effectors. Finally, simulation has been done with MATLAB /SIMULINK toolbox. The CRW UAV accelerates from helicopter mode to fixed-wing mode. Meanwhile, control loops are closed on airspeed and altitude. Simulation results show that the designed controller could meet the requirements for transition flight control.
Acute volume overload elevates T-wave alternans magnitude (2006)

The objective of this study was to determine whether acute volume loading elevates T-wave alternans (TWA) in dogs with structurally normal hearts. TWA predicts sudden cardiac arrest in patients with left ventricular dysfunction and congestive heart failure. However, volume load and ventricular stretch may themselves precipitate arrhythmias. It is unclear to what extent volume load causes TWA. In six male mongrel dogs [25.8 kg (SD 4.2)] under general anesthesia, we measured TWA during progressive atrial pacing to 160 beats/min. Pacing was performed at baseline, at the midpoint and peak of a saline infusion designed to induce acute CHF, and then during diuresis. Dog 1 was hypothermic throughout the protocol and excluded from analysis. For dogs 2-6, 102 ml/kg (SD 30) were infused over 315 min (SD 50), causing pulmonary capillary wedge pressure to rise from 9.6 (SD 3.5) to 21.2 mmHg (SD 1.6) (P < 0.01), and heart rate variability to fall (P < 0.01). TWA magnitude (Valt) rose in all dogs with volume load (P < 0.001). Compared with baseline, TWA at peak infusion had higher magnitude [Valt 3.4 (SD 1.95) vs. 0.5 muV (SD 0.35); P = 0.011] and occurred at lower heart rates [128 (SD 6) vs. 151 beats/min (SD 12); P = 0.008]. Net volume load was linearly related to Valt (P < 0.01), with each 10 ml/kg net volume load increasing Valt by 0.23 muV. Acute volume overload elevates TWA in normal canine hearts. Although dramatic, however, this effect may contribute clinically to abnormal TWA only in patients with marked volume overload. Future studies should examine the interaction of fluid overload, myocardial disease, and arrhythmia susceptibility.
Intracranial angioplasty & stenting for cerebral atherosclerosis: a position statement of the American Society of Interventional and Therapeutic Neuroradiology, Society of Interventional Radiology, and the American Society of Neuroradiology. (2005)

STROKE is the third leading cause of death and the leading cause of adult disability in North America, Europe, and Asia (1,2). Intracranial cerebral atherosclerosis accounts for approximately 8 to 10% of all ischemic strokes with a higher reported incidence in the Asian, African, and Hispanic descent populations (3–5). Risk factors include insulin-dependent diabetes mellitus, hypercholesterolemia, hypertension, and cigarette smoking (6–8). In the United States, it is estimated that 40,000 to 60,000 new strokes per year are due to intracranial cerebral atherosclerosis.
Role of adapters in Toll-like receptor signalling (2003)

Toll-like receptors (TLRs) play a critical role in the detection of invading pathogens within the body and the subsequent immune response. Individual TLRs recognize distinct microbial components. The TLRs are a type 1 transmembrane receptor that possess an extracellular leucine-rich repeat domain and cytoplasmic domain homologous with that of the interleukin 1 receptor (IL-1R) family. Upon stimulation, TLR recruits the IL-1R-associated kinase (IRAK) via the adapter MyD88, ultimately leading to the activation of nuclear factor-kappaB. Cytokine production in response to all TLR ligands is completely abolished in MyD88-deficient cells, indicating that MyD88 is an essential signalling molecule shared among members of the IL-1R/Toll family. However, several novel adaptor molecules have recently been identified. Evidence is now accumulating showing that differential utilization of these adaptors may activate overlapping as well as distinct signalling pathways, and ultimately give rise to distinct biological effects exerted by individual TLR family members.
Inhibition of Epithelial-to-Mesenchymal Transition and Pulmonary Fibrosis by Methacycline (2013)

Abstract A high-throughput small-molecule screen was conducted to identify inhibitors of epithelial–mesenchymal transition (EMT) that could be used as tool compounds to test the importance of EMT signaling in vivo during fibrogenesis. Transforming growth factor (TGF)-β1–induced fibronectin expression and E-cadherin repression in A549 cells were used as 48-hour endpoints in a cell-based imaging screen. Compounds that directly blocked Smad2/3 phosphorylation were excluded. From 2,100 bioactive compounds, methacycline was identified as an inhibitor of A549 EMT with the half maximal inhibitory concentration (IC50) of roughly 5 μM. In vitro, methacycline inhibited TGF-β1–induced α-smooth muscle actin, Snail1, and collagen I of primary alveolar epithelial cells. Methacycline inhibited TGF-β1–induced non-Smad pathways, including c-Jun N-terminal kinase, p38, and Akt activation, but not Smad or β-catenin transcriptional activity. Methacycline had no effect on baseline c-Jun N-terminal kinase, p38, or Akt activities or lung fibroblast responses to TGF-β1. In vivo, 100 mg/kg intraperitoneal methacycline delivered daily beginning 10 days after intratracheal bleomycin improved survival at Day 17 (P &amp;lt; 0.01). Bleomycin-induced canonical EMT markers, Snail1, Twist1, collagen I, as well as fibronectin protein and mRNA, were attenuated by methacycline (Day 17). Methacycline did not attenuate inflammatory cell accumulation or alter TGF-β1–responsive genes in alveolar macrophages. These studies identify a novel inhibitor of EMT as a potent suppressor of fibrogenesis, further supporting the concept that EMT signaling is important to lung fibrosis. The findings also provide support for testing the impact of methacycline or doxycycline, an active analog, on progression of human pulmonary fibrosis.
Protection of factor Xa from neutralization by the heparin-antithrombin complex. (1983)

We have studied the accessibility of Factor Xa to neutralization by the heparin-antithrombin complex within plasma and whole blood. This serine protease was detected by measuring the concentrations of activation fragments (F2/F1+2) cleaved from prothrombin. The levels of F2/F1+2) were quantitated by means of a sensitive and specific radioimmunoassay. Our findings indicate that the binding of Factor Xa to "activated" platelets but not to phospholipid micelles results in the protection of the above enzyme from inactivation by the heparin-antithrombin complex. This sequestration of Factor Xa is not affected by the liberation of platelet release proteins or the molecular heterogeneity of the mucopolysaccharide preparations used. The magnitude of enzyme protection is strongly correlated with the extent of prothrombin activation at the time of heparin addition. On this basis, we suggest that high in vivo rates of thrombin generation may lead to the sequestration of Factor Xa on the platelet surface and hence allow this serine protease to resist the action of heparin until the complex is cleared from the circulation.
A computer model of human thermoregulation for a wide range of environmental conditions: the passive system (1999)

A dynamic model predicting human thermal responses in cold, cool, neutral, warm, and hot environments is presented in a two-part study. This, the first paper, is concerned with aspects of the passive system: 1) modeling the human body, 2) modeling heat-transport mechanisms within the body and at its periphery, and 3) the numerical procedure. A paper in preparation will describe the active system and compare the model predictions with experimental data and the predictions by other models. Here, emphasis is given to a detailed modeling of the heat exchange with the environment: local variations of surface convection, directional radiation exchange, evaporation and moisture collection at the skin, and the nonuniformity of clothing ensembles. Other thermal effects are also modeled: the impact of activity level on work efficacy and the change of the effective radiant body area with posture. A stable and accurate hybrid numerical scheme was used to solve the set of differential equations. Predictions of the passive system model are compared with available analytic solutions for cylinders and spheres and show good agreement and stable numerical behavior even for large time steps.
Identification ofN-Glycans Displaying Mannose-6-Phosphate and their Site of Attachment on Therapeutic Enzymes for Lysosomal Storage Disorder Treatment (2011)

Characterization of mono- and bis-mannose-6-phosphate (M6P) bearing oligosaccharides present on acid hydrolase enzymes poses a considerable analytical challenge. In the current paper, we investigated the use of UPLC profiling on a 1.7 μm HILIC phase and capillary electrophoresis with laser induced fluorescence detection (CE-LIF) combined with exoglycosidase digestion and weak anion exchange fractionation for the characterization of M6P bearing glycans on recombinant β-glucuronidase expressed in Chinese Hamster Ovary (CHO) cells. Using this multidimensional approach a number of peaks were observed to resist digestion, suggesting the presence and blocking activity of the M6P tag. To investigate further, mixed oxide affinity purification on a combined TiO(2)/ZrO(2) resin facilitated the selective enrichment of oligosaccharides bearing mono- or diphospho-esters that corresponded to those peaks previously identified to resist exoglycosidase digestion. Alkaline phosphatase digestion identified Man(6)GlcNAc(2) and Man(7)GlcNAc(2) glycans as the primary carriers of the M6P tag. Site-specific glycoproteomic analysis revealed that Man(7)GlcNAc(2)-M6P oligosaccharides were present at asparagine 272 and 420, while asparagine 631 displayed Man(6)GlcNAc(2)-M6P. The analytical strategy applied herein represents a novel yet simple approach for the qualitative and semiquantitative structural characterization of M6P containing oligosaccharides on therapeutic enzymes.
Microwave-assisted synthesis of a new series of resorcin[4]arene cavitand-capped porphyrin capsules (2009)

Capsule-shaped molecular receptors are fundamental to the modeling of biological host-guest interactions such as those characteristic of enzymatic processes. Among the more versatile and effective synthetic receptors are the hemicarcerand-type hosts. Herein we report the synthesis of six novel resorcin[4]arene cavitand-capped porphyrin capsules, in a new series of molecular capsules modeled on the classical hemicarcerands initially reported by Cram and co-workers. In the first reported instance of its utilisation in the preparation of supramolecularly-capped porphyrin host molecules, microwave (MW) irradiation was used (in conjunction with Adler conditions) in order to form the porphyrin cap in situ. Additionally, the yields obtained via these conditions exhibited a significant improvement, relative to the traditional refluxing protocol hitherto reported. Capsules 20-25 are indefinitely stable, and we observed that 22 and 25 possess the smallest rigidified cavities yet reported for resorcin[4]arene cavitand-capped porphyrin host molecules.
Processing of mutated proinsulin with tetrabasic cleavage sites to bioactive insulin in the non‐endocrine cell line, COS‐7 (1992)

The amino acid sequence, Arg-4-X-3-Lys/Arg-2-Arg-1 decreases X+1, is thought to be a consensus processing site for a constitutive secretory pathway in non-endocrine cells. We created a mutant proinsulin DNA with a peptide structure of B chain-Arg-Arg-Lys-Arg-C peptide-Arg-Arg-Lys-Arg-A chain, which compares to the native proinsulin structure of B chain-Arg-Arg-C peptide-Lys-Arg-A chain. When the mutant insulin was expressed in a monkey kidney-derived cell line, COS-7, approximately 60% of the total immunoreactive insulin appeared as mature insulin in the culture medium. This conversion to the mature form was strikingly facilitated by co-expressing the mutant proinsulin with furin, a homologue of the yeast endoprotease, Kex2.
Stimulation of expression of the human endogenous retrovirus genome by female steroid hormones in human breast cancer cell line T47D (1987)

Expression of the human endogenous retrovirus genome HERV-K, homologous to mouse mammary tumor virus, was investigated in cultured human tumor cells. In several cell lines, the HERV-K genome was expressed as an 8.8-kilobase poly(A)+ RNA which appeared to be a full-size transcript of this genome. In the human breast cancer cell line T47D, stimulation of HERV-K genome expression by progesterone was observed after estradiol treatment.
Palladium-Catalyzed Indole and Azaindole Synthesis by Direct Annulation of Electron-Pooro-Chloroanilines ando-Chloroaminopyridines with Aldehydes (2008)

A practical process for the synthesis of 2-unsubstituted indoles and azaindoles has been developed by the palladium-catalyzed direct annulation of electron-poor o-chloro/bromoanilines and o-chloroaminopyridines with aldehydes. Coupled with the previous results of Jia and Zhu, this allows rapid access to a variety of 2-unsubstituted indoles and azaindoles starting from simple and easily accessible precursors.
Conjugation of Trypsin by Temperature-Sensitive Polymers Containing a Carbohydrate Moiety: Thermal Modulation of Enzyme Activity (1998)

Novel temperature-sensitive polymers containing glucose units in their backbone were synthesized and covalently conjugated to trypsin. A series of copolymers based on N-isopropylacrylamide (NIPAAm) and glucosyoxylethyl methacrylate (GEMA) were prepared by using 4,4'-azobis(4-cyanovaleric acid) as an initiator, which resulted in one terminal carboxylic acid group per polymer chain. The polymers were conjugated to primary amine groups of trypsin with water-soluble carbodiimide as a coupling agent, which led to a star-shaped conformation. The polymer-enzyme conjugation was confirmed and characterized by size exclusion and reversed-phase chromatography. Almost of all amine groups in trypsin available for the conjugation were consumed and, consequently, a very dense layer of copolymers was actually coated around the enzyme surface. The conjugated enzymes exhibited reversible precipitation/resolubilization behaviors over a wide range of temperatures, depending on the content of GEMA in the copolymer. They also demonstrated no detectable self-digestion (autolysis) process, but the unconjugated enzyme showed very severe autolysis that led to a rapid inactivation in aqueous solution. When bovine serum albumin was used as a substrate, the protein substrate was not attacked by the conjugated enzyme, but completely digested by the unconjugated enzyme. This result was presumably caused by a steric repulsion process of the attached polymer chains around the enzyme toward the protein substrate. However, the enzyme retained sufficient activity against a low molecular weight substrate. Interestingly, the conjugated enzymes demonstrated very peculiar enzyme activity-temperature profiles, with two apparent optimal temperatures, indicating that a temperature-controlled collapse and flocculation of the copolymers around the enzyme surface modulated the mass transfer rates of substrate to the active site of the enzyme. The conjugated enzymes also exhibited improved thermal stability with increasing the amount of carbohydrate units in the polymer chain.
Yield of Large‐Volume Blood Cultures in Patients with Early Lyme Disease (2001)

To improve yield, 6 3-mL plasma cultures (18 mL total) were established for adult patients with early Lyme disease associated with erythema migrans. Borrelia burgdorferi was recovered from the blood of 22 (44.0%) of 50 evaluable patients. The recovery rate per plasma culture and the frequency of positive results for plasma cultures for individual patients were consistent with a level of spirochetemia of approximately 0.1 cultivable cell/mL of whole blood. Our findings suggest that, if further improvements in the yield of blood cultures are possible, they probably will depend on enhancing the sensitivity of the culture method rather than increasing the volume of material cultured.