gebhart/patrepeval huggingface dataset:
Risk of malignancies associated with ustekinumab (2017)

A recently published report by Florek et al.1 associates malignancies with ustekinumab (STELARA®) treatment. Janssen emphasizes patient safety and welcomes rigorous safety analyses from other parties. However, it is unclear how this report adds to the understanding of ustekinumab's safety profile.

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Splenic CD19−CD35+B220+ cells function as an inducer of follicular dendritic cell network formation (2007)

Follicular dendritic cells (FDCs) form a reticular FDC network in the lymphoid follicle that is essential for the retention and presentation of native antigens in the form of antigen-antibody immune complexes (ICs) to B cells during secondary immune response. Although the presence of migrating precursors of FDCs has been hypothesized, their entity has not been elucidated. Here we report the identification of murine splenic CD19(-)CD11c(-)CD35(+)B220(+) cells as an inducer of FDC network formation. We demonstrated that CD19(-)-CD11c(-)CD35(+)B220(+) cells, together with stromal cells, had the remarkable ability to form lymphoid-follicle-like structures that contained B220(+)FDC-M1(+) reticular cells originally derived from CD19(-)-CD11c(-)CD35(+)B220(+) cells in the CD35(+) reticulum. Our results indicate that CD19(-)CD11c(-)CD35(+)B220(+) cells function as an inducer of FDC network formation and that the interaction between CD19(-)CD11c(-)CD35(+)B220(+) cells and stromal cells is required to initiate lymphoid follicle formation.
High Throughput Selection of Effective Serodiagnostics for Trypanosoma cruzi infection (2008)

These results substantially extend the variety and quality of diagnostic targets for Chagas disease and offer a useful tool for determining treatment success or failure.
Rapid antigenic-type replacement and DNA sequence evolution of canine parvovirus (1991)

Analysis of canine parvovirus (CPV) isolates with a panel of monoclonal antibodies showed that after 1986, most viruses isolated from dogs in many parts of the United States differed antigenically from the viruses isolated prior to that date. The new antigenic type (designated CPV type 2b) has largely replaced the previous antigenic type (CPV type 2a) among virus isolates from the United States. This represents the second occurrence of a new antigenic type of this DNA virus since its emergence in 1978, as the original CPV type (CPV type 2) had previously been replaced between 1979 and 1981 by the CPV type 2a strain. DNA sequence comparisons showed that CPV types 2b and 2a differed by as few as two nonsynonymous (amino acid-changing) nucleotide substitutions in the VP-1 and VP-2 capsid protein genes. One mutation, resulting in an Asn-Asp difference at residue 426 in the VP-2 sequence, was shown by comparison with a neutralization-escape mutant selected with a non-CPV type 2b-reactive monoclonal antibody to determine the antigenic change. The mutation selected by that monoclonal antibody, a His-Tyr difference in VP-2 amino acid 222, was immediately adjacent to residue 426 in the three-dimensional structure of the CPV capsid. The CPV type 2b isolates are phylogenetically closely related to the CPV type 2a isolates and are probably derived from a common ancestor. Phylogenetic analysis showed a progressive evolution away from the original CPV type. This pattern of viral evolution appears most similar to that seen in some influenza A viruses.
Thermal, Electrochemical, and Spectroscopic Characterizations of Hyperbranched Polymer Electrolyte (1999)

Novel polymer electrolytes have been prepared with hyperbranched polymers as the host and lithium trifluoromethanesulfonimide, , as the ion source. Analysis of the salt concentration dependence of the glass transition temperature indicates that intermolecular interactions occur in the polymer electrolytes and that these hyperbranched polymers can function as a "solvent" for the lithium salt. Two maxima were observed in the isotherm of conductivity vs. the lithium salt concentration in the polymer electrolyte by ac impedance measurements. Fourier transform infrared spectroscopic analysis of the polymer electrolytes over a large range of lithium salt concentration has been made. It is shown that these two conductivity maximas might be related to the ‐polymer coordination at low lithium salt concentration and the formation of ion pairs and higher ion aggregates at high lithium salt concentration, respectively. © 1999 The Electrochemical Society. All rights reserved.
Dose-response studies with nitrosoheptamethyleneimine and its alpha-deuterium-labeled derivative in F344 rats. (1982)

A dose-response study of the carcinogenicity of nitrosoheptamethyleneimine (N-HEP) in inbred F344 male and female rats was performed by administration of the nitrosamine at several concentrations in drinking water to groups of 20 rats. The concentrations differed by a factor of nearly 2.5 and ranged from 1.0 to 100 mg/liter. The duration of treatment was 13, 25, 50, or 100 weeks, after which the animals were allowed to die naturally of tumors induced. In most treated groups the incidence of tumors of the upper gastrointestinal tract approached 100%. However, at the higher doses there was an inverse relationship between total dose and survival time of the rats. Matched treatment of groups of rat with N-HEP labeled with deuterium in the alpha positions resulted in longer survival. The slower action of the deuterium-labeled compound, as measured by a lower rate of death from tumors, suggests that cleavage of a carbon-hydrogen bond at an alpha position is a rate-limiting step in carcinogenesis by N-HEP in rats.
Sustained Enzymatic Correction by rAAV-Mediated Liver Gene Therapy Protects Against Induced Motor Neuropathy in Acute Porphyria Mice (2010)

Acute intermittent porphyria (AIP) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (PBGD) activity. Clinical features are acute neurovisceral attacks accompanied by overproduction of porphyrin precursors in the liver. Recurrent life-threatening attacks can be cured only by liver transplantation. We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven by a liver-specific promoter to provide sustained protection against induced attacks in a predictive model for AIP. Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve. Hepatocyte transduction showed no gender variation after rAAV2/8 injection, while rAAV2/5 showed lower transduction efficiency in females than males. Full protection against induced phenobarbital-attacks was achieved in animals showing over 10% of hepatocytes expressing high amounts of PBGD. More importantly, sustained hepatic expression of hPBGD protected against loss of large-caliber axons in the sciatic nerve and disturbances in nerve conduction velocity as induced by recurrent phenobarbital administrations. These data show for the first time that porphyrin precursors generated in the liver interfere with motor function. rAAV2/5-hPBGD vector can be produced in sufficient quantity for an intended gene therapy trial in patients with recurrent life-threatening porphyria attacks.
Outage probability analysis for short-range communication systems at 60 GHz in ATT urban environments (1997)

In the context of a short-range communication system for advanced transport telematics (ATT) applications, this paper presents an analytical method to derive outage probability in the presence of Rice fading, noise, interference, and antenna diversity with selection combining; the approach is exploited to evaluate the performance of beacon-to-vehicle communications in urban environments. ATT applications are becoming more and more relevant for the purpose of designing a road traffic management system, either in urban or highway environments. The interest of researchers in this field mainly indicated two different frequency ranges for system operability, i.e., the 5.8and 60-64-GHz bands. The advantage of using millimeter waves is discussed with reference to efficient spatial filtering effects, having chosen a suitable model for channel characterization at 60 GHz. The validity of the analytical method is checked by means of Monte Carlo simulation. The role of oxygen and rain absorption on system performance is also investigated. By considering a monodimensional topology and a Manhattan scenario, system availability is evaluated in a multiuser context by taking the role of interfering signals on downlink performance into account. As an example of application, a time-division multiple-access (TDMA) scheme is assumed for channel access. The methodology exploited allows the definition of suitable design criteria; numerical results give the optimum value of distance between beacons as a function of system parameters and link budget.
5.8 GHz circular polarized rectifying antenna for microwave power transmission (2002)

This paper reports a new 5.8 GHz circular polarized (CP) high gain, high-efficiency rectifying antenna (rectenna). The CP rectenna can be rotated and still maintain a constant output voltage. A high-gain dual rhombic loop antenna and a reflecting plane are used to achieve a circular polarized antenna gain of 10.5 dB, a 2:1 VSWR bandwidth of 10 %, and average beamwidths of 43/spl deg/ and 59/spl deg/ In the E- and H-planes, respectively. The rectenna circuit has a coplanar stripline (CPS) band reject filter (BRF) which suppresses the re-radiated harmonics by 20 dB. A highly efficient Schottky diode is used for RF to DC conversion with an efficiency of approximately 80%.
The pre-clinical pharmacology of the inhaled muscarinic antagonist GSK573719 predicts once-daily clinical dosing (2011)

Introduction: GSK573719 is a new, long-acting muscarinic antagonist offering sustained 24-h bronchodilation currently in phase III clinical trials for COPD. Objectives: To assess the pharmacology of GSK573719 in pre-clinical studies. Methods/Results: In CHO cells transfected with recombinant human M 3 receptors, GSK573719 demonstrated pM potency (–log pA 2 =23.9pM) in an acetylcholine (ACh)-mediated Ca 2+ mobilisation assay. Concentration-response curves indicated competitive antagonism with partial reversibility after drug wash out. Using isolated human bronchial strips in static tissue baths, GSK573719 was a potent, competitive antagonist (–log pA 2 =316pM) vs carbachol. Superfusion of bronchial strips with carbachol containing buffer showed that GSK573719 was slowly reversible in a concentration-dependent manner (1–100nM). Time to 50% restoration of contraction at 10nM was &gt;600 min (vs 413 min with tiotropium bromide, 10nM). In conscious guinea pigs, GSK573719 dose-dependently blocked ACh-induced bronchoconstriction with long duration of action; a 2.5μg intratracheal dose elicited &gt;50% bronchoprotection for &gt;24h. Conclusions: GSK573719 is a potent muscarinic antagonist that demonstrates slow functional reversibility at cloned human M 3 receptors and at endogenous mAChR in isolated human bronchus. This profile translates into 24h duration of bronchodilation in the clinic, suitable as a once-daily treatment for COPD. Funded by GSK. *Formerly at GSK.
Calcium-regulated phosphorylation in synaptosomal cytosol: dependence on calmodulin. (1980)

Calcium stimulated the phosphorylation of several specific synaptosomal cytosolic proteins. The effects of calcium were both concentration and time dependent and were most apparent for proteins with molecular weights of 50,000, 55,000, and 60,000. Exogenous calcium (1.0-100 microM) enhanced the net incorporation of phosphate into protein by as much as 23-fold. In the absence of added calcium, the calcium chelator [ethylenebis(oxyethylenenitriolo)]tetraacetic acid did not lower the phosphorylation of any protein below control levels. The antipsychotic, fluphenazine (1.0-100 microM), caused a concentration-dependent decrease in calcium-stimulated protein phosphorylation. When the heat-stable calcium-binding protein, calmodulin, was removed from synaptosomal cytosol by affinity chromatography on fluphenazine-Sepharose, calcium-stimulated protein phosphorylation was abolished. Responsiveness to calcium could be restored by the addition of calmodulin to the phosphorylation assay. These results indicate that calcium-dependent protein kinases are of major importance in regulating the phosphorylation of specific cytosolic proteins in neuronal tissue. Furthermore, it would appear that one of the three substrates under investigation is specific to synaptosomal cytosol whereas the other two are present in both the cytosol and membrane fractions.
Ganglion cell loss in RCS rat retina: A result of compression of axons by contracting intraretinal vessels linked to the pigment epithelium (1998)

In the dystrophic Royal College of Surgeons (RCS) rat retina, there is a progressive loss of photoreceptors. As a result, the retinal circulation becomes apposed to the retinal pigment epithelium (RPE) and neovascular formations develop. RPE and inner nuclear layer cells migrate along these vessels towards the retinal ganglion cell (RGC) layer. The retinal layers gradually become disrupted, and some of the RGC axon bundles involute into the retina. These bundles are always associated with blood vessels, and there is evidence of axon damage where they juxtapose. In wholemount preparations of dystrophic retinae (> or =6 months of age), abrupt changes are observed in the trajectory of RGC axon bundles, where they are crossed by circumferential vessels. Degenerative profiles can be seen at these locations. Visualisation of RGCs with Fluoro-gold shows wedge-shaped sectors in the dystrophic retina devoid of labelling, initially in the ventral retina but later spreading dorsally. It is hypothesised that the vessels supplying the neovascular formations contract and pull surface vessels into the retina, thus displacing any axon bundles that lie beneath them into the inner plexiform layer. The contractility may be an intrinsic property of the vessels or it may be conferred by the cells migrating along them. Axonal transport becomes blocked at the points of tension, thereby causing retrograde degeneration of the parent RGCs. Because RGC loss is also a feature of human retinitis pigmentosa, the RCS rat may provide a model to test interventions devised to prevent such loss following photoreceptor degeneration. This model also may be useful for testing methods designed to control blood vessel and matrix formation.
Low‐light imaging technology in the life sciences (1994)

Photon imaging is an increasingly important technique for the measurement and analysis of chemiluminescence and bioluminescence. New high-performance low-light level imaging systems have recently become available for the life sciences. These systems use advances in camcera design and digital image processing and are now being used for a wide range of luminescence applications. They offer good sensitivity for photon detection and large dynamic range, and are suitable for quantitative analysis. This is achieved using a range of software techniques including image arithmetic, histogramming or summing regions of interest, feature extraction and multiple image processing for kinetics or assay screening. Improvements in image-processing hardware and software have increased the usefulness of these systems in the biosciences. Low-light imaging is a rapid and non-invasive method for the sensitive detection and analysis of luminescent assays. As such it offers a powerful and sensitive tool for investigating processes, both at the cellular level (luc and lux reporter genes, intracellular signalling) and for measurement of macro samples (immunoassays, gels and blots, tissue sections).
Trastuzumab — Mechanism of Action and Use in Clinical Practice (2007)

Overexpression of human epidermal growth factor receptor type 2 (HER2) in breast cancer is associated with decreased overall survival. Trastuzumab, a humanized monoclonal antibody that targets HER2, is approved by the Food and Drug Administration for patients with invasive breast cancers that overexpress HER2. This review considers the mechanism of action and the use of this agent.
Peptidyl Aldehydes as Reversible Covalent Inhibitors of Protein Tyrosine Phosphatases (2002)

Protein tyrosine phosphatases (PTPs) are a large family of enzymes that catalyze the hydrolytic removal of the phosphoryl group from phosphotyrosyl (pY) proteins. PTP inhibitors provide potential treatment of human diseases/conditions such as diabetes and obesity as well as useful tools for studying the function of PTPs in signaling pathways. In this work, we have shown that certain aryl-substituted aldehydes act as reversible, slow-binding inhibitors of modest potency against PTP1B, SHP-1, and a dual-specificity phosphatase, VHR. Attachment of the tripeptide Gly-Glu-Glu to the para position of cinnamaldehyde resulted in an inhibitor (Cinn-GEE) of substantially increased potency against all three enzymes (e.g., KI* = 5.4 μM against PTP1B). The mechanism of inhibition was investigated using Cinn-GEE specifically labeled with 13C at the aldehyde carbon and 1H-13C heteronuclear single-quantum coherence spectroscopy. While Cinn-GEE alone showed a single cross-peak at δ 9.64 (1H) and δ 201 (13C), the PTP1B/Cinn-GEE complex showed three distinct cross-peaks at δ 7.6−7.8 (1H) and 130−137 (13C). Mutation of the catalytic cysteine (Cys-215 in PTP1B) into alanine had no effect on the cross-peaks, whereas mutation of a conserved active-site arginine (Arg-221 in PTP1B) to alanine abolished all three cross-peaks. Similar experiments with Cinn-GEE that had been labeled with 13C at the benzylic position revealed a change in the hybridization state (from sp2 to sp3) for the benzylic carbon as a result of binding to PTP1B. These results rule out the possibility of a free aldehyde, aldehyde hydrate, or hemithioacetal as the enzyme-bound inhibitor form. Instead, the data are consistent with the formation of an enamine between the aldehyde group of the inhibitor and the guanidine group of Arg-221 in the PTP1B active site. These aldehydes may provide a general core structure that can be further developed into highly potent and specific PTP inhibitors.
Synthesis and Processing of Genetically Modified Human Proinsulin by Rat Myoblast Primary Cultures (1996)

Rat myoblast primary cultures were tested as a model for proinsulin synthesis and processing and unregulated insulin delivery for insulin-dependent diabetes mellitus (IDDM) gene therapy. Three human proinsulin cDNA constructs containing genetically engineered furin endoprotease cleavage sites between the B-chain and C-peptide (IFur) and between the C-peptide and A-chain (IIFur) and/or containing a histidine B10 to aspartic acid point mutation were subcloned into a mammalian expression vector (pCMV) containing the cytomegalovirus (CMV) promoter. The altered cleavage sites enable the insulin to be processed by the ubiquitous endoprotease furin. The histidine B10 to aspartic acid mutation creates a more stable form of insulin leading to an increase in insulin accumulation. Myoblasts transfected with a proinsulin cDNA construct mutated at all three sites (pCMV.IFur.IIFur.B10), a construct with only the furin sites (pCMV.IFur.IIFur), and a construct containing only the mutation at the B10 position (pCMV.B10) accumulated 852 +/- 16, 150 +/- 13, and 883 +/- 39 microU (pro)insulin/ml, respectively, in the culture medium during a 48-hr incubation. (Pro)insulin was detected in the culture medium within 2 hr post-transfection. Significant (pro)insulin release continued for 1 week and gradually diminished over a month. Approximately 50% of the proinsulin released from rat myoblasts transfected with pCMV.IFur.IIFur.B10 was completely processed into mature insulin based on densitometric analysis of autoradiographs of gels containing immunoprecipitated 35S-Cys-labeled (pro)insulin. However, only a trace of the proinsulin encoded by pCMV.B10 was processed. In an isolated rat adipocyte [14C]glucose oxidation assay, insulin released from myoblasts transfected with pCMV.IFur.IIFur.B10 was active biologically, displaying more biological activity than normal human insulin. Plasmid expression was studied by transfecting myoblasts with the beta-galactosidase (beta-Gal) gene in pCMV, allowing them to divide and fuse into multinucleated myotubes, followed by staining for beta-Gal. Approximately 80% of myotubes expressed beta-Gal. The results indicate that proinsulin encoded by genetically modified proinsulin cDNA is processed into mature insulin, which is secreted at high levels, making myoblasts a viable target cell for gene therapy of IDDM.
The architecture of a fault-tolerant cached RAID controller (1993)

RAID-5 arrays need 4 disk accesses to update a data block—2 to read old data and parity, and 2 to write new data and parity. Schemes previously proposed to improve the update performance of such arrays are the Log-Structured File System [10] and the Floating Parity Approach [6]. Here, we consider a third approach, called Fast Write, which eliminates disk time from the host response time to a write, by using a Non-Volatile Cache in the disk array controller. We examine three alternatives for handling Fast Writes and describe a hierarchy of destage algorithms with increasing robustness to failures. These destage algorithms are compared against those that would be used by a disk controller employing mirroring. We show that array controllers require considerably more (2 to 3 times more) bus bandwidth and memory bandwidth than do disk controllers that employ mirroring. So, array controllers that use parity are likely to be more expensive than controllers that do mirroring, though mirroring is more expensive when both controllers and disks are considered.
Structure of anti-FLAG M2 Fab domain and its use in the stabilization of engineered membrane proteins (2006)

The inherent difficulties of stabilizing detergent-solubilized integral membrane proteins for biophysical or structural analysis demand the development of new methodologies to improve success rates. One proven strategy is the use of antibody fragments to increase the ;soluble' portion of any membrane protein, but this approach is limited by the difficulties and expense associated with producing monoclonal antibodies to an appropriate exposed epitope on the target protein. Here, the stabilization of a detergent-solubilized K(+) channel protein, KvPae, by engineering a FLAG-binding epitope into a known loop region of the protein and creating a complex with Fab fragments from commercially available anti-FLAG M2 monoclonal antibodies is reported. Although well diffracting crystals of the complex have not yet been obtained, during the course of crystallization trials the structure of the anti-FLAG M2 Fab domain was solved to 1.86 A resolution. This structure, which should aid future structure-determination efforts using this approach by facilitating molecular-replacement phasing, reveals that the binding pocket appears to be specific only for the first four amino acids of the traditional FLAG epitope, namely DYKD. Thus, the use of antibody fragments for improving the stability of target proteins can be rapidly applied to the study of membrane-protein structure by placing the short DKYD motif within a predicted peripheral loop of that protein and utilizing commercially available anti-FLAG M2 antibody fragments.