gebhart/patrepeval huggingface dataset:
Targeted Degradation of Proteins by Small Molecules: A Novel Tool for Functional Proteomics† (2004)

A novel strategy that targets protein for degradation has recently been developed by exploiting a protein-targeting chimeric molecule ('Protac'). Typically, the chimeric Protac is composed of a small-molecule ligand ('bait') on one end and a synthetic octapeptide on the other. This octapeptide is recognized by E3 ubiquitin ligase pVHL (von Hippel Lindau tumor suppressor protein), thereby recruiting a small molecule-bound protein ('prey') to pVHL for ubiquitination and degradation. Since selective degradation of a cellular protein generates a "loss of function" mutation, this protein knock-out strategy may be useful to study the function of a given protein or to evaluate whether a cellular protein is a potential target for drug intervention, in a manner reminiscent of gene knock-out or siRNA approaches. Herein, we show that a synthetic pentapeptide is sufficient to interact with pVHL E3 ligase, and that the pentapeptide-based Protac efficiently induces ubiquitination and degradation of target protein. Our results also demonstrate that the pentapeptide-based Protac can enter cells efficiently to exerts its biological activity effectively. These results suggest that the synthetic pentapeptide can be used either directly in the preparation of cell-permeable Protacs or as a template to develop peptidomimetic or non-peptide Protacs.
Increased interleukin 8 expression in the colon mucosa of patients with inflammatory bowel disease. (1996)

To test whether there is a difference in the expression of interleukin 8 (IL8) between Crohn's disease and ulcerative colitis and to determine the main site of its synthesis this study analysed IL8 in mucosal biopsy specimens of patients with Crohn's disease and ulcerative colitis by enzyme linked immunosorbent assay (ELISA) and by in situ hybridisation. IL8 was measured by ELISA in 38 normal control patients, eight inflammatory control patients, 55 Crohn's disease biopsy specimens (26 patients), and 67 ulcerative colitis biopsy specimens (35 patients). IL8 mRNA was determined in samples by in situ hybridisation using a specific IL8 RNA probe. IL8 protein was significantly increased in macroscopically inflamed specimens of Crohn's disease (median 118 pg/specimen, p < 0.0001), ulcerative colitis (median 140 pg/specimen, p < 0.001), and inflammatory controls (median 30 pg/specimen, p = 0.010) compared with normal controls (median 4 pg/specimen). IL8 was also increased in uninflamed specimens of Crohn's disease (median 46 pg/specimen, p < 0.001) but not of ulcerative colitis patients (median 9 pg/specimen, p = 0.3). IL8 protein in the mucosa correlated significantly with macroscopic inflammation in Crohn's disease (r = 0.47, p < 0.001) and in ulcerative colitis (r = 0.60, p < 0.001). IL8 mRNA was detected by in situ hybridisation in 31 of 55 biopsy specimens (56%) of Crohn's disease patients, in 38 of 67 specimens of ulcerative colitis patients (57%), in five of eight inflammatory controls (63%) and in five of 38 normal controls (13%). Mucosal IL8 mRNA expression correlated with mucosal IL8 protein (r = 0.46, p < 0.001). IL8 mRNA was only detected in inflammatory cells of the interstitium but not in mucosal epithelial cells. IL8 is produced mainly in the lamina propria of the colon in inflammatory bowel disease and correlates with mucosal inflammation.
13C nuclear magnetic resonance studies of the biosynthesis by Microbacterium ammoniaphilum of L-glutamate selectively enriched with carbon-13. (1982)

13C NMR of isotopically enriched metabolites has been used to study the metabolism of Microbacterium ammoniaphilum, a bacterium which excretes large quantities of L-glutamic acid into the medium. Biosynthesis from 90% [1-13C]glucose results in relatively high specificity of the label, with [2,4-13C2]glutamate as the major product. The predominant biosynthetic pathway for synthesis of glutamate from glucose was determined to be the Embden Meyerhof glycolytic pathway followed by P-enolpyruvate carboxylase and the first third of the Krebs cycle. Different metabolic pathways are associated with different correlations in the enrichment of the carbons, reflected in the spectrum as different 13C-13C scalar multiplet intensities. Hence, intensity and 13C-13C multiplet analysis allows quantitation of the pathways involved. Although blockage of the Krebs cycle at the alpha-ketoglutarate dehydrogenase step is the basis for the accumulation of glutamate, significant Krebs cycle activity was found in glucose grown cells, and extensive Krebs cycle activity in cells metabolizing [1-13C]acetate. In addition to the observation of the expected metabolites, the disaccharide alpha, alpha-trehalose and alpha, beta-glucosylamine were identified from the 13C NMR spectra.
Activin/Nodal signalling in stem cells (2015)

Activin/Nodal growth factors control a broad range of biological processes, including early cell fate decisions, organogenesis and adult tissue homeostasis. Here, we provide an overview of the mechanisms by which the Activin/Nodal signalling pathway governs stem cell function in these different stages of development. We describe recent findings that associate Activin/Nodal signalling to pathological conditions, focusing on cancer stem cells in tumorigenesis and its potential as a target for therapies. Moreover, we will discuss future directions and questions that currently remain unanswered on the role of Activin/Nodal signalling in stem cell self-renewal, differentiation and proliferation.
Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells. (1994)

The phosphorylation and dephosphorylation of proteins on tyrosyl residues are key regulatory mechanisms in T-cell signal transduction and are controlled by the opposing activities of protein tyrosine kinases and phosphotyrosyl phosphatases (PTPs). In T cells, several nontransmembrane protein tyrosine kinases are associated with receptors; for example, Lck is bound to the coreceptors CD4 and CD8 and becomes activated upon their stimulation. In comparison, little is known about the role of nontransmembrane PTPs in early T-cell signaling. SH-PTP1 (PTP1C, HCP, SHP) is a nontransmembrane PTP expressed primarily in hematopoietic cells, including T cells. We have found that SH-PTP1 is basally phosphorylated on serine in resting T cells. Upon stimulation of CD4 or CD8 either in a T-cell hybridoma cell line or in primary thymocytes, SH-PTP1 becomes tyrosyl phosphorylated. Moreover, SH-PTP1 is constitutively phosphorylated on tyrosine in the Lck-overexpressing lymphoma cell line LSTRA. SH-PTP1 is also a good substrate for recombinant Lck in vitro. Comparisons of the tryptic phosphopeptide maps of wild-type SH-PTP1 and deletion and point mutations establish that the two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. One of these sites (Y-564) is phosphorylated in T cells in response to Lck activation. We conclude that SH-PTP1 undergoes Lck-dependent tyrosyl phosphorylation in T cells and likely plays a role in early T-cell signaling.
The Adaptive Brain: Aging and Neurocognitive Scaffolding (2008)

There are declines with age in speed of processing, working memory, inhibitory function, and long-term memory, as well as decreases in brain structure size and white matter integrity. In the face of these decreases, functional imaging studies have demonstrated, somewhat surprisingly, reliable increases in prefrontal activation. To account for these joint phenomena, we propose the scaffolding theory of aging and cognition (STAC). STAC provides an integrative view of the aging mind, suggesting that pervasive increased frontal activation with age is a marker of an adaptive brain that engages in compensatory scaffolding in response to the challenges posed by declining neural structures and function. Scaffolding is a normal process present across the lifespan that involves use and development of complementary, alternative neural circuits to achieve a particular cognitive goal. Scaffolding is protective of cognitive function in the aging brain, and available evidence suggests that the ability to use this mechanism is strengthened by cognitive engagement, exercise, and low levels of default network engagement.
Multi-Microphone Neural Speech Separation for Far-Field Multi-Talker Speech Recognition (2018)

This paper describes a neural network approach to far-field speech separation using multiple microphones. Our proposed approach is speaker-independent and can learn to implicitly figure out the number of speakers constituting an input speech mixture. This is realized by utilizing the permutation invariant training (PIT) framework, which was recently proposed for single-microphone speech separation. In this paper, PIT is extended to effectively leverage multi-microphone input. It is also combined with beamforming for better recognition accuracy. The effectiveness of the proposed approach is investigated by multi-talker speech recognition experiments that use a large quantity of training data and encompass a range of mixing conditions. Our multi-microphone speech separation system significantly outperforms the single-microphone PIT. Several aspects of the proposed approach are experimentally investigated.
The Role of Genetic Toxicology in Drug Discovery and Optimization (2008)

Genetic toxicology data is used as a surrogate for long-term carcinogenicity data during early drug development. The aim of genotoxicity testing is to identify potentially hazardous drug candidates. Results from genetic toxicology tests in combination with acute and subchronic animal data are used as the basis to approve clinical trials of drug candidates. With few exceptions, mutagenic compounds are dropped from development and clastogenic compounds result in unfavorable labeling, require disclosure in clinical trial consent forms, and can impact the marketability of a new drug. Therefore, genetic toxicology testing in drug discovery and optimization serves to quickly identify mutagens and remove them from development. Additionally, clastogenicity can delay drug development by requiring additional testing to determine in vivo relevance of in vitro clastogenic responses. Clastogenicity screening is conducted so any additional testing can be planned and perhaps integrated into other toxicity studies to expedite progression of drugs into the clinic. Commercially available genotoxicity and carcinogenicity predictive software systems used for decision support by ICSAS, FDA/CDER is described along with the strengths and weakness of each system. The FDA has concentrated on using a consensus approach to maximize certainty for positive predictions at the expense of sensitivity. The consensus approach consists of requiring 2 complementary software packages, such as MC4PC and MDL QSAR models, to agree that a compound has a genotoxic or carcinogenic liability. Mutagenicity and clastogenicity screening tests are described along with advantages and disadvantages of each test. Several testing strategies are presented for consideration.
Mapping of chromosomal imbalances in pancreatic carcinoma by comparative genomic hybridization. (1996)

To identify recurrent chromosomal imbalances in pancreatic adenocarcinoma, 27 tumors were analyzed by using comparative genomic hybridization. In 23 cases chromosomal imbalances were found. Gains of chromosomal material were much more frequent than losses. The most common overrepresentations were observed on chromosomes 16p (eight cases), 20q (seven cases), 22q (six cases), and 17q (five cases) and under-representations on a subregion of chromosome 9p (eight cases). Distinct high-level amplifications were found on 1p32-p34, 6q24, 7q22, 12p13, and 22q. These data provide evidence for a number of new cytogenetically defined recurrent aberrations which are characteristic of pancreatic carcinoma. The overrepresented or underrepresented chromosomal regions represent candidate regions for potential oncogenes and tumor suppressor genes, respectively, possibly involved in pancreatic tumorigenesis.
Effect of SR49059, an orally active V1a vasopressin receptor antagonist, in the prevention of dysmenorrhoea (2000)

This study showed for the first time a therapeutic effect of an orally active vasopressin V1a receptor antagonist in the prevention of dysmenorrhoea. Further studies are required to examine effect mechanisms and determine effective doses.
Antibody‐targeted superantigen therapy induces tumor‐infiltrating lymphocytes, excessive cytokine production, and apoptosis in human colon carcinoma (1996)

Bacterial superantigens are the most potent known activators of human T lymphocytes. To engineer superantigens for immunotherapy of human colon carcinoma, the superantigen, staphylococcal enterotoxin A (SEA) was genetically fused to the Fab region of the colon carcinoma-reactive monoclonal antibody C242. In the present study the effector mechanisms involved in the anti-tumor response to C242 Fab-SEA were characterized. Immunohistochemistry and computer-aided image analysis were used in studies of cryopreserved tumor tissue to evaluate the phenotype of infiltrating cells and their cytokine profiles in response to therapy. Human T cells and monocytes were recruited to the tumor area and penetrated the entire tumor mass within hours after injection of C242 Fab-SEA. The production of cytokines at the single-cell level was found to be dominated by tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor, and transforming growth factor-beta, whereas IL-1-alpha, IL-1ra, IL-1 beta, TNF-beta, IL-3, IL-6, and IL-8 were undetectable. Most of the TNF-alpha, IL-2, IL-12, and IFN-gamma were made by the infiltrating human leukocytes, while the colon carcinoma cells were induced to produce IL-4, IL-10, and TNF-alpha. Up-regulation of IFN-gamma receptors and TNF R p60 receptors was found, while the TNF R p80 receptor was absent. The cytokine production, T cell infiltration, and CD95 Fas receptor expression concomitantly occurred to induce programmed cell death in the tumor cells. This was followed by a strong reduction of the tumor mass that was seen within 24 h after C242 Fab-SEA infusion. These findings demonstrate that antibody-superantigen proteins efficiently recruit tumor-infiltrating lymphocytes actively producing a variety of cytokines likely to be essential for the therapeutic effects observed in the model. Although the humanized SCID model has obvious limitations in its predictive value for treatment of human cancer, we believe that these results encourage clinical evaluation of antibody-targeted superantigens.
CD8+ regulatory T cells in solid organ transplantation (2010)

CD8 Treg cells represent a subset of regulatory T cells with great potential for future therapeutic application and researchers are moving ahead for a better understanding of their action in antigraft immune response suppression.
The Determination of 11-nor- 9-Tetrahydrocannabinol-9-Carboxylic Acid (THC-COOH)in Hair using Negative Ion Gas Chromatography-Mass Spectrometry and High-Volume Injection (2001)

The determination of 11-nor-delta9-THC-9-carboxylic acid (THC-COOH) in hair specimens at the sensitivity required to detect marijuana users is a difficult analytical problem. A sensitive and specific method has been developed for the quantitative assay of THC-COOH in hair. Hair specimens were washed, incubated in sodium hydroxide, subjected to solid-phase extraction, and analyzed using high-volume injection coupled with negative chemical ionization (NCI) mass spectrometry. A common disadvantage of chemical ionization, the production of a single mass-to-charge ratio ion, was also addressed. By specific selection of the derivatizing agent, three ions were monitored, allowing the calculation of two ion ratios, as in electron impact mode. The method was applied to several hair specimens taken from known marijuana users and workplace specimens. This is the first publication describing the use of high-volume injection and NCI mass spectrometry for the determination of THC-COOH in hair.
Heterocyclization Reactions with Carbodimides: Synthesis of Fused 1,2,4-Triazoles (1986)

Reactions de N-amino heterocycles avec des diarylcarbodiimides: obtention de triazoles-1,2,4 condenses; dans quelques cas, isolement des intermediaires heteryl-2 guanidines qui se cyclisent en triazoles-1,2,4 condenses neutres ou mesoioniques
DNA–Based Immunization for Asthma (1999)

ISS is most effective in inhibiting airway eosinophilia when administered as a single dose 6 days prior to antigen inhalation. However, ISS can also significantly inhibit eosinophilic inflammation, when coadministered with antigen inhalation. Thus, ISS administered prior or together with allergen should be considered as a novel method of allergen-based immunotherapy.
370: Micro-RNAS Profiling in Kidney and Bladder Cancers (2005)

INTRODUCTION AND OBJECTIVE: Active form of vitamin D3, 1,25(0H)2D3 shows various action such as suppression of cell growth, induction of differentiation, immunoregulation besides calcium metabolic regulation. We previously reported that suppression of mouse renal carcinoma cell (RENCA) by 1,25(0H)2D. 1,25(0H)z03 are mediated by binding to a nuclear high-affinity receptor (VDR) in complex with the 9-cis-retinoic acid receptor (RXR). The activated VDR-RXR complex binds to a vitamin D response element (VDRE) located in the promoters of some genes (p21 , hTERTetc). We investigated whether expression of the VDR gene and RXR gene can be associated with renal cell carcinoma (RCC).
Three-Dimensional Integrated Circuits and the Future of System-on-Chip Designs (2006)

Three-dimensional integrated circuits (3-D ICs) offer significant improvements over two-dimensional circuits, and promise a solution to the severe problems that are being, and will be, encountered as monolithic process geometries are reduced to below 65 nm. Several methods associated with the fabrication of 3-D ICs are discussed in this paper, and the techniques developed by Tezzaron Semiconductor Corp., are described in detail. Four successful 3-D ICs are described, along with the anticipated benefits of applying 3-D design to future system-on-chip (SoC) devices.
Adaptive modelling and forecasting of offshore wind power fluctuations with Markov‐switching autoregressive models (2010)

ABSTRACT Wind power production data at temporal resolutions of a few minutes exhibit successive periods with fluctuations of various dynamic nature and magnitude, which cannot be explained (so far) by the evolution of some explanatory variable. Our proposal is to capture this regime‐switching behaviour with an approach relying on Markov‐switching autoregressive (MSAR) models. An appropriate parameterization of the model coefficients is introduced, along with an adaptive estimation method allowing accommodation of long‐term variations in the process characteristics. The objective criterion to be recursively optimized is based on penalized maximum likelihood, with exponential forgetting of past observations. MSAR models are then employed for one‐step‐ahead point forecasting of 10 min resolution time series of wind power at two large offshore wind farms. They are favourably compared against persistence and autoregressive models. It is finally shown that the main interest of MSAR models lies in their ability to generate interval/density forecasts of significantly higher skill. Copyright © 2010 John Wiley &amp; Sons, Ltd.
Geomaterial‐Functionalized Microfluidic Devices Using a Universal Surface Modification Approach (2019)

Abstract The layer‐by‐layer (LbL) self‐assembly technique is used to coat the surface of flow channels in microfluidic chips with geomaterials. The surface modifications diminish the discrepancy between the surface chemistry of synthesized microfluidic devices and those of underground porous rocks. Hence, the use of visual models and, in particular, microfluidic devices is broadened to simulate the multiphase flows and fluid–solid interactions in actual rocks. Glass and quartz substrates are successfully coated with silicon dioxide (SiO 2 ), bentonite, and montmorillonite. On‐chip functionalization of polydimethylsiloxane (PDMS) and glass micromodels with SiO 2 is also accomplished. The functionalized coatings using confocal laser scanning microscopy (CLSM), atomic force microscopy (AFM), and contact angle measurements are characterized. The surface modification technique is shown to be material‐independent, which generates a hydrophilic surface. The surface‐coated chips, functionalized by clay particles, are utilized to illustrate the role of water salinity on oil displacement.
The role of CD40-CD40 ligand interaction in human T cell-B cell collaboration. (1994)

Interactions between CD40 on B cells and its ligand on activated T cells have been reported to play an important role in T cell-B cell collaboration. In this current study, a mAb against the human CD40 ligand (5c8) was used to investigate the impact of CD40-CD40 ligand interactions in the initial activation of normal human peripheral blood B cells and in subsequent proliferation and differentiation. B cells were activated by co-culture with anti-CD3-stimulated normal T cells. mAb against CD40 ligand blocked initial T cell-dependent B cell activation, as assessed by [3H]uridine incorporation and IL-2R expression. Subsequent B cell proliferation and differentiation were also inhibited by this mAb. In addition to its effect on B cell activation, 5c8 also inhibited the capacity of B cells to augment IL-2 production by anti-CD3 activated T cells, implying a role for CD40-CD40 ligand interactions in the accessory function of B cells. Despite the importance of CD40-CD40 ligand interactions in T cell-B cell collaboration, CD40 ligand-deficient T cell clones were found to induce initial activation of B cells and support Ig production. This effect was only marginally effected by mAb to LFA-1 and ICAM-1, suggesting that additional interaction molecules play a role in T cell-B cell collaboration. Taken together, the data indicate that CD40-CD40 ligand interactions plays an important role in T cell-dependent B cell activation and subsequent differentiation but additional interaction structures are also involved in T cell-B cell collaboration.