gebhart/patrepeval huggingface dataset:
Transforming growth factor alpha (TGF alpha) expression in degenerating motoneurons of the murine mutant wobbler: a neuronal signal for astrogliosis? (1994)

The enhanced expression of the trophic factor transforming growth factor alpha (TGF alpha) in reactive astrocytes following CNS injury suggests that TGF alpha has a role in the development of astrogliosis. We explored this hypothesis in the murine mutant wobbler, which presents a progressive motoneuronal degeneration associated with an astrogliosis. Evolution of astrogliosis, and expression of TGF alpha precursor (pro-TGF alpha) and of its receptor were examined over the course of the disease, using genetically diagnosed animals and immunocytochemical techniques. We report here that degenerating motoneurons of the cervical spinal cord and a subset of astrocytes express pro-TGF alpha, prior to the onset of astrogliosis, when the first clinical manifestations of the disease are observed at 4 weeks of age. TGF alpha expression appeared strongly correlated with motoneuronal degeneration. All pro-TGF alpha-immunoreactive neurons exhibited a degenerative morphology, and the number of pro-TGF alpha-immunoreactive neurons increased with the progression of the disease. At the glial level, we observed that astrogliosis was a transitory phenomenon in the wobbler mice, developing in coordination with the motoneuronal expression of pro-TGF alpha. Astrogliosis became evident in 6-week-old wobbler mice, when the number of pro-TGF alpha-immunoreactive motoneurons was maximal, and regressed in older mutant mice in correlation with the disappearance of pro-TGF alpha-immunoreactive motoneurons. Furthermore, TGF alpha/EGF receptor immunoreactivity was exclusively localized in a subset of reactive astrocytes, its expression following closely the course of the astrogliosis. These data show that TGF alpha synthesis by the affected motoneurons is an early event in the course of the wobbler disease, and suggest a role for TGF alpha as a neuronal inducer of astrocytic reactivity.
Genetic Interaction of Flavivirus Nonstructural Proteins NS1 and NS4A as a Determinant of Replicase Function (1999)

Nonstructural protein 1 (NS1) of yellow fever virus (YF) is a glycoprotein localized to extracytoplasmic compartments within infected cells. We have previously shown that NS1 can be supplied in trans and is required for viral RNA replication, a process thought to occur in membrane-bound cytoplasmic complexes. Here we report that the NS1 gene from a related virus, dengue virus (DEN), is unable to function in the process of YF RNA replication. This virus-specific incompatibility leads to a lack of initial minus-strand accumulation, suggesting that DEN NS1 is unable to productively interact with the YF replicase. Based on a YF deletion mutant that requires NS1 in trans, a genetic screen for suppressor mutants was used to select virus variants able to utilize DEN NS1. In three independent selections, a single mutation was mapped to the NS4A gene, which encodes a putative transmembrane replicase component. This mutation, as well as several additional mutations, was engineered into the NS1-deficient genome and confirmed a genetic interaction between NS1 and NS4A. These findings suggest a potential mechanism for integrating NS1 into the cytoplasmic process of RNA replication.
Membrane surface antigen expression on neutrophils: a reappraisal of the use of surface markers for neutrophil activation (1991)

Neutrophil research relies largely on studies with highly purified cells. Yet the isolation procedures induce changes in surface expression of several proteins. We used a large panel of monoclonal antibodies (MoAbs) to characterize in detail the phenotypic changes during isolation and stimulation of human neutrophils. Centrifugation on density gradients appears to be the crucial step that causes an increase in expression of antigens not detectable on neutrophils in whole blood samples (cytochrome b558 recognized by MoAb 7D5; and CD10) or expressed at significantly lower levels (CD11a, CD11b, CD11c, CD13, CD16, CD45, and CD67). Other antigens were unaffected by the density gradient centrifugation step (CD32, CD54, CD58, Leu-8, HLA class I). Upregulation of antigens was also determined by stimulation of purified neutrophils. Upregulation of CD63 was an excellent marker for release from azurophil granules. We subsequently related the surface antigen expression to functional activities of purified neutrophils. From these experiments, we concluded that 7D5-as "early activation" marker--does not necessarily discriminate between primed or resting neutrophils with respect to NADPH oxidase activity.
Molecular Biomarkers for Breast Cancer Prognosis: Coexpression of c-erbB-2 and p53 (2001)

These data suggest that c-erbB-2 and p53 expression in breast cancer have prognostic significance. After median follow-up of 16 years, coexpression of c-erbB-2 and p53 may have more prognostic significance than traditional prognostic factors such as T stage and nodal status. Prospective study of large numbers of patients with breast cancer is encouraged to validate these findings.
IO performance prediction in consolidated virtualized environments (abstracts only) (2011)

We propose a trace-driven approach to predict the performance degradation of disk request response times due to storage device contention in consolidated virtualized environments. Our performance model evaluates a queueing network with fair share scheduling using trace-driven simulation. The model parameters can be deduced from measurements obtained inside Virtual Machines (VMs) from a system where a single VM accesses a remote storage server. The parameterized model can then be used to predict the effect of storage contention when multiple VMs are consolidated on the same virtualized server. The model parameter estimation relies on a search technique that tries to estimate the splitting and merging of blocks at the the Virtual Machine Monitor (VMM) level in the case of multiple competing VMs. Simulation experiments based on traces of the Postmark and FFSB disk benchmarks show that our model is able to accurately predict the impact of workload consolidation on VM disk IO response times.
Multicyclic Peptides as Scaffolds for the Development of Tumor Targeting Agents (2017)

The lack of specificity of traditional cytotoxic drugs triggers the development of anticancer agents with high selectivity to tumor-specific proteins. The unveiling of target structures such as EGFR or Her2 allows the focused development of novel therapies and has strongly advanced tumor treatment. Tumor-specific high-affinity ligands can be identified by using display techniques such as phage, yeast surface, ribosome and mRNA display. These techniques enable the screening of huge libraries, consequently providing a valuable alternative to rational drug development. In recent years, miniproteins and multicyclic peptides have become the preferred ligands expressed by these libraries. Due to their favorable pharmacokinetics and the ease of their synthesis, peptidic ligands overcome disadvantages of antibody derived therapeutics. Peptides that are structurally defined by a rigid scaffold are ideally suited for the use in display techniques. These molecules feature high stability and excellent affinities while offering the opportunity to randomize partial sequences to be used as binding sites. Structurization of the peptide scaffold can be achieved by different approaches, of which cyclization is one of the most commonly used. The favored cyclization strategies are based on amide or disulfide bridging and the use of synthetic braces or chemical linkers. The use of multicyclic peptides allows the simultaneous presentation of several different binding loops. Semisynthetic approaches enable the introduction of unnatural amino acids, increasing the diversity of the resulting peptide libraries. Given that, miniprotein scaffolds offer a wide range of potential applications and facilitate efficient screening of novel high-affinity ligands to be used in precise diagnosis and highly efficient cancer therapy. Keywords: Drug development, miniprotein scaffolds, targeted therapy, peptide libraries, display techniques, highaffinity ligands.
Ruminococcus gnavus Total Hip Arthroplasty Infection in a 62-Year-Old Man with Ulcerative Colitis (2015)

We report the case of a total hip arthroplasty infection caused by Ruminococcus gnavus in a 62-year-old man with ulcerative colitis. The bacterium was perfectly identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry.
Immunotherapy in neuromuscular disorders: Current and future strategies (1996)

Autoimmune mechanisms have recently been implicated in the pathogenesis of an increasing number of neuromuscular diseases. Many of these diseases can be treated with immunotherapeutic agents that are currently available--often with striking success. However, lack of specificity and adverse side effects impose limits on the effectiveness of these immunosuppressive treatments. This article reviews the basic principles of autoimmunity and immune tolerance, and outlines strategies that produce (a) generalized immunosuppression; (b) "selective" immunotherapy; and (c) "antigen-specific" immunotherapy. General immunosuppressive treatments, which are the ones most commonly used in current practice, down-regulate the immune system at multiple levels in "shotgun" fashion. The agents described here include: adrenal corticosteroids, azathioprine, cyclophosphamide, chlorambucil, methotrexate, total lymphoid irradiation, plasmapheresis, and intravenous immunoglobulin. "Selective" immunotherapeutic strategies are designed to interfere with mechanisms intrinsic to the immune system. Agents that are now being used clinically, or are in advanced stages of development include: cyclosporin A, which interferes with synthesis of the cytokine interleukin 2 (IL2); IL2 toxin, which binds to IL2 receptors on activated T cells, is endocytosed, and kills the cells; and CTLA4Ig, which blocks costimulatory molecules, thus preventing full activation of T cells. We have found that combinations of the selective agents may enhance their effectiveness. "Specific" strategies are designed to inactivate or suppress antigen-specific T cells. Oral administration of autoantigens has been shown to prevent experimental autoimmune diseases specifically, but the conditions required to suppress ongoing autoimmune diseases are capricious, and depend on many factors. Finally, we describe a method that is still in the experimental stage, which is designed to modify the individual's own antigen-presenting cells so that they will target and inactivate antigen-specific T cells, and thereby turn off the specific autoimmune response. Currently available immunosuppressive methods can now be used successfully to treat many autoimmune neuromuscular diseases, and the application of selective and specific immunotherapeutic strategies promises more precise and effective treatment in the future.
Smoking-related differenzial CpG methylation: a 27k discovery and replication study (2010)

Background: Tobacco smoking-associated diseases are a health problem of global scale. Epigenetic patterns including CpG methylation have been implicated in smoking-related pathology. Here, we present a genome-wide methylation study of smoking behaviour. Methods: The discovery round was conducted in 177 participants (current, former, and never smokers) of the epidemiological ESTHER study. Another 316 subjects served as an independent replication sample. Methylation patterns were analysed in peripheral blood DNA using the Infinium HumanMethylation27 BeadChip microarray. Validation and replication were done by Sequenom MassArray. Results: A single locus showed genome-wide significance for differenzial methylation by smoking behaviour in the discovery round, when using either parametric or non-parametric statistical methods. This finding was validated using the Sequenom assay and successfully replicated in the independent sample set. Conclusions: This genome-wide screen for differences in CpG methylation by smoking status identified a gene which might plausibly be involved in tobacco-related pathophysiology. Additional studies will have to address the functional implications of this finding for gene expression and clinical endpoints.
Synthesis of Prostaglandin E2 Ethanolamide from Anandamide by Cyclooxygenase-2 (1997)

Because of its structural similarity to polyunsaturated fatty acids, anandamide could serve as substrate for enzymes such as lipoxygenases and cyclooxygenases, which metabolize polyunsaturated fatty acids to potent bioactive metabolites. Here the ability of recombinant human cyclooxygenase-1 (hCOX-1) and cyclooxygenase-2 (hCOX-2) to metabolize anandamide was studied. Baculovirus-expressed and -purified hCOX-2, but not hCOX-1, effectively oxygenated anandamide. Reverse phase high pressure liquid chromatography analysis of the products derived from 1-14C-labeled anandamide showed that the products formed are similar to those formed with arachidonic acid as substrate. The major prostanoid product derived from anandamide was determined by mass spectrometry to be prostaglandin E2 ethanolamide. Incubation of anandamide with lysates and the intact cell line expressing COX-2 but not that of COX-1 produced prostaglandin E2 ethanolamide. These results demonstrate the existence of a COX-2-mediated pathway for anandamide metabolism, and the metabolites formed represent a novel class of prostaglandins.
Shape-Specific Detection Based on Fluorescence Resonance Energy Transfer Using a Flexible Water-Soluble Conjugated Polymer (2006)

We present the detection of the shape-specific conformation of DNA based on the fluorescence resonance energy transfer (FRET) by using a novel flexible water-soluble cationic conjugated polymer (CCP). The flexible backbone of CCP has more conformational freedom with the potential to be responsive to analyte shape by electrostatic interaction between flexible CCP and negatively charged DNA. The analyte shape dependent recognition is accomplished by structural changes that compressed or extended the flexible CCP. The morphology-dependent spectral properties of the novel flexible polymer related to the analyte shapes are investigated in detail, where two types of chromophores, referred to as "isolated" segment and "packed" segment aggregates, within the flexible polymer are identified by means of ensemble and single molecule measurements upon binding with different geometric DNA. The change in fluorescence intensity upon binding with shape-specific DNA without obvious color shifts makes this novel flexible polymer a suitable CCP donor for FRET measurements. The results provide insights for understanding the spectral properties of flexible water-soluble CCP and CCP/DNA interaction related to the geometry of target analyte.
Reaction of 5-Halocytosine Derivatives with Cysteine (1988)

Abstract 5-Bromo-(1) and 5-iodo-2′-deoxycytidine (2) undergo 100 percent dehalogenation to 2′-deoxycytidine on heating with cysteine in IN aq K2CO3 in a nitrogen atmosphere at 50° for 72 h and 21 h, respectively. 5-Chloro-2′-deoxycytidine (3) and 1-methyl-5-chlorocytosine (3m) on the other hand undergo very little dehalogenation, forming instead two products, 4, 5 and 4m, 5m respectively, whose structures have been determined by mass spectrometry and proton magnetic resonance spectroscopy of the 3m products: 1-methyl-5-(cystein-S-yl)cytosine (4m) and 3-methyl-2,6,7,8 -tatrahydro-2-oxo-3H-pyrimido [5,4-b][1,4]-thiazine-7-carboxylic acid (5m), mp. 236°C, 78 percent yield. Initially produced 4m undergoes a novel and facile cyclization to form 5m with loss of NH3 in the presence of cysteine. The compound 3m, mp. 258°C, has been synthesized by treating 1-methylcytosine with N-chlorosuccinimide in acetic acid at 105° for 3 h in 56 percent yield. Ultraviolet absorption spectral properties of 1, 2, 3, 3m, 4, 4m, 5, and 5m are reported.
The flaky skin (fsn) mutation in mice: map location and description of the anemia (1995)

Flaky skin (gene symbol fsn) is an autosomal recessive mutation that causes pleiotropic effects of anemia, papulosquamous skin disorder, and gastric forestomach hyperplasia. In this report, we assign fsn to distal chromosome 17 and characterize the anemia. The decrease in hematocrit levels and red blood cell counts is significant and persists throughout life in fsn/fsn mice. There is compensatory enlargement of the heart, liver, and spleen by 8 weeks of age, whereas the thymus is less than one half normal weight. Nucleated cell counts in the peripheral blood are increased 15- to 30-fold, primarily due to an increased percentage of normoblasts. The fsn/fsn mice examined at 8 weeks of age have significantly increased reticulocyte counts and protoporphyrin levels but reduced hemoglobin concentration, suggesting possible abnormalities of hemoglobin metabolism. Erythrocyte membrane fragility is normal. Compared with normal +/? littermates, fsn/fsn mice (1) lack splenic and hepatic stores of elemental iron, (2) have the ability to transport 59Fe across the duodenal cells and into the blood, (3) have increased levels of transferrin in serum, and (4) have acute loss of urinary 59Fe. Hemolysis is indicated by increased serum bilirubin and high blood reticulocyte numbers. Collectively, the genetic, hematologic, and pathologic data indicate a severe hematologic disorder caused by homozygosity for the fsn mutation that differs from other known hematologic mutations in the mouse. The mechanism whereby fsn induces the reported pleiotropic effects has yet to be elucidated.
Rosa26 Locus Supports Tissue-Specific Promoter Driving Transgene Expression Specifically in Pig (2014)

Genetically modified pigs have become a popular model system in fundamental research, agricultural and biomedical applications. However, random integration often result in unstable expression of transgene and unpredictable phenotypes. The Rosa26 locus has been widely used to produce genetic modified animals with high and consistent expressing of transgene in mouse, human and rat, as it can be targeted efficiently and is not subject to gene-silencing effects. Recently, the first case of reporter gene targeting pigs in porcine Rosa26 (pRosa26) locus was reported. In the study, full sequence of pRosa26 locus was further characterized, and the pRosa26 promoter (pR26) was cloned and we evidenced that the new porcine endogenous promoter is suitable for driving transgene expression in a high and stable manner by avoiding DNA methylation. Furthermore, elongation factor 1a promoter (EF1a) -driven GFP reporter and Myostatin promoter (MyoP)-driven Follistatin (Fst) were successfully targeted into the pRosa26 locusby traditional homologous recombination (HR) strategy. EF1a showed high activity and hypomethylation at the locus. And, muscle-specific promoter MyoP was activated strictly in muscle of the pRosa26 targeted pigs, indicating Rosa26 locus supports tissue-specific promoter driving transgene expression in its own manner. The study provided further demonstration on biomedical and agricultural applications of porcine Rosa26 promoter and locus.
Physical modeling of the step recovery diode for pulse and harmonic generation circuits (1969)

A simple charge-controlled switching model describes most fundamental aspects of the step recovery diode. However, it is shown that switching speed and the associated loss are related to the width of the i layer and to the doping level. A switching model appropriate for general computer use is given, and examples of its application are shown in pulse and harmonic generator circuits.
An Inactivated Cell-Culture Vaccine against Yellow Fever (2011)

A two-dose regimen of the XRX-001 vaccine, containing inactivated yellow fever antigen with an alum adjuvant, induced neutralizing antibodies in a high percentage of subjects. XRX-001 has the potential to be a safer alternative to live attenuated 17D vaccine. (Funded by Xcellerex; ClinicalTrials.gov number, NCT00995865.).
Multiple-bit long-term data storage by backward-stimulated echo in Eu^3+:YAlO_3 (1989)

We have observed faithful storage and retrieval of multiple data pulses for up to 5 h in Eu(3+):YAlO(3) crystal by using the backward-stimulated echo. We find no loss of echo fidelity as the storage time is increased. Furthermore the lack of cross talk between the input data pulses suggests that faithful long-term storage and retrieval of a large number of data pulses are possible. Our measured echo-storage lifetime of 3.8 h is to our knowledge the longest reported thus far.
Quadratic-backtracking algorithm for string reconstruction from substring compositions (2014)

Motivated by the problem of deducing the structure of proteins using mass-spectrometry, we study the reconstruction of a string from the multiset of its substring compositions. We specialize the backtracking algorithm used for the more general turnpike problem for string reconstruction. Employing well known results about transience of random walks in ≥ 3 dimensions, we show that the algorithm reconstructs random strings over alphabet size ≥ 4 with high probability in near-optimal quadratic time.
A new array architecture for parallel testing in VLSI memories (2003)

The authors describe a novel array architecture and its application to a 16-Mb DRAM (dynamic random-access memory) suitable for the line mode test (LMT) with test circuits consisting of a multipurpose register (MPR) and a comparator. The LMT can test all memory cells connected to a word line simultaneously. Testing with random patterns along a word line is easily realized by using the MPR as a pattern register after setting random test data in the MPR. Test time is reduced to approximately 1/1000. Owing to the MPR, the present LMT can achieve flexible testing with high fault coverage. The excess area penalty due to the circuits for the LMT is suppressed within 0.5% in application to the 16-Mb DRAM.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
G Proteins in Drug Screening: From Analysis of Receptor-G Protein Specificity to Manipulation of GPCR-Mediated Signalling Pathways (2006)

Seven transmembrane G protein coupled receptors (7TM GPCRs) represent one of the largest gene familes in the human genome. Because of the size of the GPCR family, their proven history of being valuable targets for small molecule drug design, the fact that the absolute number of GPCRs that are targets for current medicines represents only a small fraction of the total encoded by the human genome, and that ligands for GPCRs do not have to enter the cell to exert their function, it is very likely that GPCRs will remain major targets for the pharmaceutical industry in the foreseeable future. Despite recent evidence indicating that GPCRs can provide information to cells, that does not require activation of G proteins ("signaling at zero G"), most of the GPCRs known to date function via interaction with and activation of heterotrimeric (alphabetagamma) G proteins. Thus, assay systems translating ligand modulation of GPCRs into G protein-dependent intracellular responses are a key component of both basic research and the drug discovery process. This article will review the current knowledge and recent progress in understanding molecular aspects of specific receptor-G protein recognition. It will also highlight how the knowledge generated by such studies can be transformed into assay systems for GPCR drug discovery.
4,5-Diphenyltriazol-3-ones:  Openers of Large-Conductance Ca2+-Activated Potassium (Maxi-K) Channels (2002)

A series of diphenyl-substituted heterocycles were synthesized and evaluated by electrophysiological techniques as openers of the cloned mammalian large-conductance, Ca(2+)-activated potassium (maxi-K) channel. The series was designed from deannulation of known benzimidazolone maxi-K opener NS-004 (2) thereby providing an effective template for obtaining structure-activity-related information. The triazolone ring system was the most studied wherein 4,5-diphenyltriazol-3-one 6d (maxi-K = 158%) was identified as the optimal maxi-K channel opener.