gebhart/patrepeval huggingface dataset:
In silico Pathway Activation Network Decomposition Analysis (iPANDA) as a method for biomarker development (2016)

Signalling pathway activation analysis is a powerful approach for extracting biologically relevant features from large-scale transcriptomic and proteomic data. However, modern pathway-based methods often fail to provide stable pathway signatures of a specific phenotype or reliable disease biomarkers. In the present study, we introduce the in silico Pathway Activation Network Decomposition Analysis (iPANDA) as a scalable robust method for biomarker identification using gene expression data. The iPANDA method combines precalculated gene coexpression data with gene importance factors based on the degree of differential gene expression and pathway topology decomposition for obtaining pathway activation scores. Using Microarray Analysis Quality Control (MAQC) data sets and pretreatment data on Taxol-based neoadjuvant breast cancer therapy from multiple sources, we demonstrate that iPANDA provides significant noise reduction in transcriptomic data and identifies highly robust sets of biologically relevant pathway signatures. We successfully apply iPANDA for stratifying breast cancer patients according to their sensitivity to neoadjuvant therapy.
Pyrazole Urea-Based Inhibitors of p38 MAP Kinase:  From Lead Compound to Clinical Candidate (2002)

We report on a series of N-pyrazole, N'-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5'-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.
Steroid Modulation of Astrocytes in the Neonatal Brain: Implications for Adult Reproductive Function (2002)

There is a growing appreciation for the importance of astrocytes, a type of nonneuronal glial cell, to overall brain functioning. The ability of astrocytes to respond to gonadal steroid hormones with changes in morphology has been well documented in the adult brain. It is also apparent that astrocytes of the developing brain are permanently differentiated by the neonatal hormonal milieu, in particular by estradiol, resulting in sexually dimorphic cell morphology, synaptic patterning, and density in males and females. The mechanisms of hormonally mediated astrocyte differentiation are likely to be region specific. In the arcuate nucleus of the hypothalamus, neuron-to-astrocyte signaling appears to play a critical role in estradiol-induced astrocyte differentiation during the first few days of life. Gamma aminobutyric acid (GABA) is an amino acid neurotransmitter that is synthesized and released exclusively by neurons. The levels of GABA are increased in the arcuate nucleus of neonatal males versus females. Preventing the increase in males or mimicking GABA action in females modulates astrocytes accordingly. Speculation about and evidence in support of the functional significance of this dimorphism to adult reproductive functioning is the topic of this review.
The Role of the Toxicologic Pathologist in the Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (1999)

Biotechnology-derived pharmaceuticals, or biopharmaceuticals, represent a special class of complex, high molecular weight products, such as monoclonal antibodies, recombinant proteins, and nucleic acids. With these compounds, it is not appropriate to follow conventional safety testing programs, and the preclinical "package" for each biopharmaceutical needs to be individually designed. In addition to standard histopathology, the use of molecular pathology techniques is often required either in conventional animal studies or in in vitro tests. In this review, the safety evaluation of biopharmaceuticals is discussed from the perspective of the toxicologic pathologist, and appropriate examples are given of the use of molecular pathology procedures. Examples include the use of in situ hybridization to localize gene therapy vectors, the assessment of vector integration into genomic DNA by the polymerase chain reaction (PCR), and the use of immunohistochemistry to evaluate the potential cross-reactivity of monoclonal antibodies. In situ PCR techniques may allow for confirmation of the germ cell localization of nucleic acids and may therefore facilitate the risk assessment of germline transmission. Increased involvement with biopharmaceuticals will present challenging opportunities for the toxicologic pathologist and will allow for much greater use of molecular techniques, which have a critical role in the preclinical development of these compounds.
Protein Kinase Activity in Erythrocyte Ghosts of Patients with Myotonic Muscular Dystrophy (1973)

Myotonic muscular dystrophy is a disorder of humans that involves many organ systems. Physiological studies have suggested that the fundamental defect is of membrane origin. Heretofore, no reproducible metabolic abnormalities have been demonstrated. In the present studies we used erythrocyte ghosts as a convenient source of purified membranes that do not possess changes of denervation, dystrophy, and fibrosis that might complicate the interpretation of muscle membrane changes. Our experiments demonstrated a significant difference in the phosphorylation of erythrocyte ghost protein by [gamma-(32)P]ATP, with endogenous protein kinase of erythrocyte membrane as the enzyme source. After ghosts were kept for 1 week at -20 degrees , phosphorylation of membrane protein in eight controls was twice as high as endogenous protein kinase activity measured in fresh preparations. No stimulation was seen in preparations from seven myotonic dystrophy patients from three different families. This reproducible difference in normal and myotonic membranes may represent an important new approach to studies of this debilitating inborn error of metabolism.
Biphasic Catalyzed Telomerization of Butadiene and Ammonia: Kinetics and New Ligands for Regioselective Reactions (1999)

The kinetics of the palladium-catalyzed biphasic telomerization of butadiene and ammonia (shown here) was studied. From the results, a model for the reaction mechanism explaining the regioselectivities obtained was deduced. Several water-soluble phosphanes were used as ligands in this reaction, confirming the model. In one case the target product 1 was obtained with 94 % regioselectivity.
Pancreas development is promoted by cyclopamine, a Hedgehog signaling inhibitor (1998)

Exposure to cyclopamine, a steroid alkaloid that blocks Sonic hedgehog (Shh) signaling, promotes pancreatic expansion in embryonic chicks. Heterotopic development of pancreatic endocrine and exocrine structures occurs in regions adjacent to the pancreas including stomach and duodenum, and insulin-producing islets in the pancreas are enlarged. The homeodomain transcription factor PDX1, required for pancreas development, is expressed broadly in the posterior foregut but pancreas development normally initiates only in a restricted region of PDX1-expressing posterior foregut where endodermal Shh expression is repressed. The results suggests that cyclopamine expands the endodermal region where Shh signaling does not occur, resulting in pancreatic differentiation in a larger region of PDX1-expressing foregut endoderm. Cyclopamine reveals the capacity of a broad region of the posterior embryonic foregut to form pancreatic cells and provides a means for expanding embryonic pancreas development.
Fiber Bragg grating technology fundamentals and overview (1997)

The historical beginnings of photosensitivity and fiber Bragg grating (FBG) technology are recounted. The basic techniques for fiber grating fabrication, their characteristics, and the fundamental properties of fiber gratings are described. The many applications of fiber grating technology are tabulated, and some selected applications are briefly described.
Jolly SAD (2002)

Examples of phasing macromolecular crystal structures based on single-wavelength anomalous dispersion (SAD) show that this approach is more powerful and may have more general application in structural biology than was anticipated. Better data-collection facilities and cryogenic techniques, coupled with powerful programs for data processing, phasing, density modification and automatic model building, means that the SAD approach may gain wide popularity owing to its simplicity, less stringent wavelength requirements and faster data collection and phasing than the multi-wavelength (MAD) approach. It can be performed at any wavelength where anomalous scattering can be observed, in many cases using laboratory X-ray sources.
Mini Review (2004)

Since the purification of BDNF in 1982, a great deal of evidence has mounted for its central roles in brain development, physiology, and pathology. Aside from its importance in neural development and cell survival, BDNF appears essential to molecular mechanisms of synaptic plasticity. Basic activity-related changes in the central nervous system are thought to depend on BDNF modification of synaptic transmission, especially in the hippocampus and neocortex. Pathologic levels of BDNF-dependent synaptic plasticity may contribute to conditions such as epilepsy and chronic pain sensitization, whereas application of the trophic properties of BDNF may lead to novel therapeutic options in neurodegenerative diseases and perhaps even in neuropsychiatric disorders.
Viral pathogen discovery (2013)

Viral pathogen discovery is of critical importance to clinical microbiology, infectious diseases, and public health. Genomic approaches for pathogen discovery, including consensus polymerase chain reaction (PCR), microarrays, and unbiased next-generation sequencing (NGS), have the capacity to comprehensively identify novel microbes present in clinical samples. Although numerous challenges remain to be addressed, including the bioinformatics analysis and interpretation of large datasets, these technologies have been successful in rapidly identifying emerging outbreak threats, screening vaccines and other biological products for microbial contamination, and discovering novel viruses associated with both acute and chronic illnesses. Downstream studies such as genome assembly, epidemiologic screening, and a culture system or animal model of infection are necessary to establish an association of a candidate pathogen with disease.
Specificity of immunoglobulin E and immunoglobulin G against human (recombinant DNA) insulin in human insulin allergy and resistance. (1987)

Using an enzyme-linked immunosorbent assay method, we have demonstrated immunoglobulin E (IgE) and immunoglobulin G (IgG) against human (recombinant DNA) insulin in serum samples of a patient whose insulin therapy was only with human insulin. Within 12 days of initiation of human insulin for gestational diabetes, large local reactions developed in the patient in association with high levels of IgE to human insulin. As the local reactions subsided, the levels of IgE to human insulin decreased. The patient's insulin requirement was unusually high for pregnancy and tended to decrease in parallel with falling levels of IgG to human insulin, suggesting an element of immunologic insulin resistance. In addition to IgE and IgG against human insulin, we were able to demonstrate the presence of IgE and IgG against porcine and bovine insulin in the serum samples of this patient. The patient had similar immediate cutaneous reactivity to each insulin. In inhibition studies, similar amounts of porcine insulin, bovine insulin, or human insulin were found to produce 50% inhibition of human insulin binding to IgE or IgG against human insulin. Excess porcine insulin or bovine insulin resulted in total inhibition of human insulin binding to IgE or IgG. Thus even in a patient whose initial form of insulin therapy was human insulin, there was development of insulin allergy and of IgG to human insulin that may have contributed to insulin resistance. Moreover, the antigenic determinants recognized by antibody induced by human insulin may also be present on bovine insulin and porcine insulin as demonstrated in this case.
In situ isolation of mRNA from individual plant cells: creation of cell-specific cDNA libraries. (1995)

A method for isolating and cloning mRNA populations from individual cells in living, intact plant tissues is described. The contents of individual cells were aspirated into micropipette tips filled with RNA extraction buffer. The mRNA from these cells was purified by binding to oligo(dT)-linked magnetic beads and amplified on the beads using reverse transcription and PCR. The cell-specific nature of the isolated mRNA was verified by creating cDNA libraries from individual tomato leaf epidermal and guard cell mRNA preparations. In testing the reproducibility of the method, we discovered an inherent limitation of PCR amplification from small amounts of any complex template. This phenomenon, which we have termed the "Monte Carlo" effect, is created by small and random differences in amplification efficiency between individual templates in an amplifying cDNA population. The Monte Carlo effect is dependent upon template concentration: the lower the abundance of any template, the less likely its true abundance will be reflected in the amplified library. Quantitative assessment of the Monte Carlo effect revealed that only rare mRNAs (< or = 0.04% of polyadenylylated mRNA) exhibited significant variation in amplification at the single-cell level. The cDNA cloning approach we describe should be useful for a broad range of cell-specific biological applications.
Spatially resolved, highly multiplexed RNA profiling in single cells (2015)

Knowledge of the expression profile and spatial landscape of the transcriptome in individual cells is essential for understanding the rich repertoire of cellular behaviors. Here, we report multiplexed error-robust fluorescence in situ hybridization (MERFISH), a single-molecule imaging approach that allows the copy numbers and spatial localizations of thousands of RNA species to be determined in single cells. Using error-robust encoding schemes to combat single-molecule labeling and detection errors, we demonstrated the imaging of 100 to 1000 distinct RNA species in hundreds of individual cells. Correlation analysis of the ~10(4) to 10(6) pairs of genes allowed us to constrain gene regulatory networks, predict novel functions for many unannotated genes, and identify distinct spatial distribution patterns of RNAs that correlate with properties of the encoded proteins.
Localization of the apoptosis-inducing activity of lupus anticoagulant in an annexin V-binding antibody subset. (1998)

Lupus anticoagulant (LAC) is associated with arterial and venous thrombosis, thrombocytopenia, and recurrent fetal loss. We have reported previously that plasma with LAC activity induces apoptosis in endothelial cells and binds annexin V (Nakamura, N., Y. Shidara, N. Kawaguchi, C. Azuma, N. Mitsuda, S. Onishi, K. Yamaji, and Y. Wada. 1994. Biochem. Biophys. Res. Commun. 205:1488-1493). In this study, we separated two IgG antibody fractions, one with and one without affinity for annexin V, from 10 patients with LAC. LAC and apoptotic activities were localized in the annexin V-binding fraction in all 10 patients. DNA fragmentation was dose-dependent, paralleling the amount of IgG added to the human umbilical vein endothelial cell culture medium, and was inhibited by preincubation with annexin V. Removal of the antiphospholipid antibodies from patient IgG with phospholipid liposomes did not abolish the apoptosis-inducing activities or binding to annexin V. These results imply that patients with LAC often have antibodies that do not bind phospholipids and are responsible for the induction of apoptosis in endothelial cells.
INVITATION PAPER (C.P. ALEXANDER FUND): HISTORY OFBACILLUS THURINGIENSISBERLINER RESEARCH AND DEVELOPMENT (1992)

Abstract This review article starts with the discovery of Bacillus thuringiensis Berliner in Japan at the turn of the century and notes that the observations of the early Japanese workers clearly show that they were aware of the toxin-mediated nature of the activity of B . thuringiensis toward insect larvae. The early work in Europe with B . thuringiensis against Ostrinia nubilalis (Hubner) showed that the bacterium had promise as a microbial control agent. The commercial development of B . thuringiensis in France in the late 1930s, and in Eastern Europe and the United States in the 1950s, is traced.
An estimation technique for accurately modeling the magnetic recording channel including nonlinearities (1989)

A channel model called modified superposition and dan estimation technique for the parameters of this model are presented to model the magnetic recording channel including nonlinearities. It is shown that this model and estimation technique can describe the magnetic recording channel including nonlinearities much more accurately than simple superposition with isolated transient response. Computer software was developed to extract automatically the three nonlinear parameters from a single measured waveform. As an example of the usefulness of this estimation technique, experiments were conducted on a 1300 Oe, 3*10/sup -3/ emu/cm/sup 2/ thin-film disk using a 3380E 18-turn thin-film head at 70 mA pk-pk current and 23 m/s velocity.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
A 2.3 mu m/sup 2/ memory cell structure for 16 Mb NAND EEPROMs (2002)

A NAND structure memory cell with 2.2*1.05 mu m/sup 2/ size per bit, based on a 0.6 mu m design rule, has been developed for 16 Mb flash EEPROMs. The cell size is about 64% of the smallest 16 Mb EPROM cell so far reported. An extremely small cell can be realized by the following technologies: (1) newly developed 0.3 mu m space self-aligned stacked gate patterning, (2) a NAND structured cell array which contains 16 memory transistors in series, and (3) high-voltage field isolation technology used to isolate neighboring bits. The first and second technologies reduce the length of the cell by 67.6% compared with the conventional NAND structured cell using the same design rule, while the third technology reduces the width by 84.6%.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
The Suicidal Ideation Attributes Scale (SIDAS): Community‐Based Validation Study of a New Scale for the Measurement of Suicidal Ideation (2014)

While suicide prevention efforts are increasingly being delivered using technology, no scales have been developed specifically for web-based use. The Suicidal Ideation Attributes Scale (SIDAS) was developed and validated as a brief, web-based measure for severity of suicidal ideation, using an online survey of Australian adults (n = 1,352). The SIDAS demonstrated high internal consistency and good convergent validity. Frequency and controllability of thoughts were more strongly associated with suicide plans and attempts than other attributes assessed. Scores ≥ 21 indicated high risk of suicide behavior. The SIDAS appears to be a valid web-based measure for severity of suicidal ideation.
Sequence Variations of MicroRNAs in Human Cancer: Alterations in Predicted Secondary Structure Do Not Affect Processing (2006)

Expression levels of microRNAs (miRNAs) are globally reduced in cancer compared with matched normal tissues, and miRNA function has recently been implicated in tumorigenesis. To test whether epigenetic silencing contributes to miRNA suppression in tumors, lung cancer cells were treated with inhibitors of DNA methylation or histone deacetylation. No significant alteration in miRNA expression was detected using microarray profiling. To search for tumor-associated mutations that could affect processing and expression of mature miRNAs, a panel of 91 cancer-derived cell lines was analyzed for sequence variations in 15 miRNAs implicated in tumorigenesis by virtue of their known target transcripts (let-7 family targeting oncogenic Ras) or their localization to sites of frequent chromosomal instability (miR-143, miR-145, miR-26a-1, and miR-21). No mutations were detected within any of the short mature miRNA sequences. In addition to previously reported polymorphisms, 1 sequence variant in a precursor miRNA and 15 variants in primary miRNA (pri-miRNA) transcripts were identified. Despite pri-miRNAs having dramatic changes in the predicted secondary folding structure flanking putative cleavage sites, processing and miRNA maturation were not affected in vivo. Thus, genetic variants in miRNA precursors are common in cancer cells but are unlikely to have physiologic significance.
Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (2008)

In ALLHAT, with adjudicated outcomes, chlorthalidone significantly reduced the occurrence of new-onset hospitalized HFPEF and HFREF compared with amlodipine and doxazosin. Chlorthalidone also reduced the incidence of new-onset HFPEF compared with lisinopril. Among high-risk hypertensive men and women, HFPEF has a better prognosis than HFREF.
Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants (2005)

Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies.
Rituximab inhibits B-cell receptor signaling (2009)

Rituximab (RTX), a monoclonal antibody directed against the CD20 protein, is a drug commonly used in the treatment of B-cell-derived lymphoid neoplasias and of antibody-mediated autoimmune diseases. In addition to cell- and complement-mediated B-cell depletion, RTX is thought to inhibit B-cell survival and proliferation through negative regulation of canonical signaling pathways involving Akt, ERK, and mammalian target of rapamycin. However, surprisingly, although B-cell receptor (BCR) signaling has been considered critical for normal and more recently, for neoplastic B cells, the hypothesis that RTX could target BCR has never been investigated. Using follicular lymphoma cell lines as models, as well as normal B cells, we show here, for the first time, that pretreatment with RTX results in a time-dependent inhibition of the BCR-signaling cascade involving Lyn, Syk, PLC gamma 2, Akt, and ERK, and calcium mobilization. The inhibitory effect of RTX correlates with decrease of raft-associated cholesterol, complete inhibition of BCR relocalization into lipid raft microdomains, and down-regulation of BCR immunoglobulin expression. Thus, RTX-mediated alteration of BCR expression, dynamics, and signaling might contribute to the immunosuppressive activity of the drug.