gebhart/patrepeval huggingface dataset:
Intracellular Maturation of the Mouse Metalloprotease Disintegrin MDC15 (1998)

Metalloprotease disintegrins are a family of membrane-anchored glycoproteins that play a role in fertilization, myoblast fusion, neuronal development, and cleavage of the membrane-anchored cytokine tumor necrosis factor-alpha. Here, we report the cloning and cDNA sequencing of the mouse metalloprotease disintegrin MDC15 and an analysis of its processing in the secretory pathway. A notable difference between mMDC15 and its putative human orthologue (hMDC15, metargidin) is the presence of the peptide sequence TDDC instead of the RGDC found in the disintegrin domain of hMDC15. In a Western blot analysis the majority of mMDC15 was found to lack the pro-domain in all mouse tissues examined. Pulse-chase experiments in transiently transfected COS-7 cells suggest that mMDC15 is processed by a pro-protein convertase in a late Golgi compartment, since (i) addition of brefeldin A or monensin blocks pro-domain removal, (ii) all detectable processed mMDC15 is endoglycosidase H -resistant, and (iii) a recombinant soluble form of the trans-Golgi network pro-protein convertase furin can mimic mMDC15 processing in vitro. Cell-surface trypsinization revealed that more than half of mature mMDC15 is intracellular. Immunolocalization provided evidence for a strong perinuclear accumulation in a region resembling the trans-Golgi network and/or endosomal compartments. This study provides the first characterization of the intracellular processing of a metalloprotease disintegrin, and highlights the potential role of pro-protein convertases in removal of the inhibitory pro-domain. These results further suggest possible intracellular functions for mMDC15, such as in protein maturation, in addition to a potential role in cell-surface proteolysis or cell adhesion.
Hemagglutinin Variants of Reovirus Type 3 Have Altered Central Nervous System Tropism (1983)

Variants of the Dearing strain of reovirus type 3 with antigenically altered hemagglutinin proteins are much less neurovirulent than the parental virus. When injected intracerebrally into mice these variants infected a subset of the brain neurons that were infected by the parental virus. When injected intraperitoneally, the variants did not spread to the brain. These results indicate that minor modifications of the reovirus hemagglutinin dramatically alter the ability of the virus to spread into and injure the central nervous system.
The Bromodomain Protein Brd4 Stimulates G1 Gene Transcription and Promotes Progression to S Phase (2008)

Brd4 is a bromodomain protein that binds to acetylated chromatin. It regulates cell growth, although the underlying mechanism has remained elusive. Brd4 has also been shown to control transcription of viral genes, whereas its role in transcription of cellular genes has not been fully elucidated. Here we addressed the role of Brd4 in cell growth and transcription using a small hairpin (sh) RNA approach. The Brd4 shRNA vector stably knocked down Brd4 protein expression by approximately 90% in NIH3T3 cells and mouse embryonic fibroblasts. Brd4 knockdown cells were growth impaired and grew more slowly than control cells. When synchronized by serum starvation and released, Brd4 knockdown cells were arrested at G(1), whereas control cells progressed to S phase. In microarray analysis, although numerous genes were up-regulated during G(1) in control cells, many of these G(1) genes were not up-regulated in Brd4 knockdown cells. Reintroduction of Brd4 rescued expression of these G(1) genes in Brd4 knockdown cells, allowing cells to progress toward S phase. Chromatin immunoprecipitation analysis showed that Brd4 was recruited to the promoters of these G(1) genes during G(0)-G(1) progression. Furthermore, Brd4 recruitment coincided with increased binding of Cdk9, a component of P-TEFb and RNA polymerase II to these genes. Brd4 recruitment was low to absent at genes not affected by Brd4 shRNA. The results indicate that Brd4 stimulates G(1) gene expression by binding to multiple G(1) gene promoters in a cell cycle-dependent manner.
Accumulation of the inhibitory receptor EphA4 may prevent regeneration of corticospinal tract axons following lesion (2006)

Abstract We have examined the expression of Eph receptors and their ephrin ligands in adult rat spinal cord before and after lesion. Neurons in adult motor cortex express EphA4 mRNA, but the protein is undetectable in uninjured corticospinal tract. In contrast, after dorsal column hemisection EphA4 protein accumulates in proximal axon stumps. One of the ligands for EphA4, ephrinB2, is normally present in the grey matter flanking the corticospinal tract but after injury is markedly up-regulated in astrocytes in the glial scar. The result is that, after a lesion, corticospinal tract axons bear high levels of EphA4 and are surrounded to front and sides by a continuous basket of cognate inhibitory ephrin ligand. We suggest that a combination of EphA4 accumulation in the injured axons and up-regulation of ephrinB2 in the surrounding astrocytes leads to retraction of corticospinal axons and inhibition of their regeneration in the weeks after a spinal lesion.
Machine learning and systems genomics approaches for multi-omics data (2017)

In light of recent advances in biomedical computing, big data science, and precision medicine, there is a mammoth demand for establishing algorithms in machine learning and systems genomics (MLSG), together with multi-omics data, to weigh probable phenotype-genotype relationships. Software frameworks in MLSG are extensively employed to analyze hundreds of thousands of multi-omics data by high-throughput technologies. In this study, we reviewed the MLSG software frameworks and future directions with respect to multi-omics data analysis and integration. Our review was targeted at researching recent approaches and technical solutions for the MLSG software frameworks using multi-omics platforms.
Production of alpha 1,3‐Galactosyltransferase gene‐deficient pigs by somatic cell nuclear transfer: A novel selection method for gal alpha 1,3‐Gal antigen‐deficient cells (2008)

The objective of the present study was to isolate alpha 1,3-galactosyltransferase (GalGT)-gene double knockout (DKO) cells using a novel simple method of cell selection method. To obtain GalGT-DKO cells, GalGT-gene single knockout (SKO) fetal fibroblast cells were cultured for three to nine passages and GalGT-null cells were separated using a biotin-labeled IB4 lectin attached to streptavidin-coated magnetic beads. After 15-17 days of additional cultivation, seven GalGT-DKO cell colonies were obtained from a total of 2.5 x 10(7) GalGT-SKO cells. A total of 926 somatic nuclear transferred embryos reconstructed with the DKO cells were transferred into eight recipient pigs, producing four farrowed, three liveborns, and six stillborns. Absence of GalGT gene in the cloned pigs was confirmed by PCR and Southern blotting. Flow cytometric analysis revealed that alphaGal antigens were not present in the cells of the cloned DKO pigs.
Biodegration of s-triazine xenobiotics (1987)

Biodegradation of xenobiotic compounds is examined with s-triazines as an example and with biological treatment of wastewater containing striazines as an aim. s-Triazines have been termed recalcitrant, but examination of the literature indicates that a potential for biodegradation exists. Nitrogen-limited enrichment cultures yield organisms able to degrade by-products of the industrial synthesis of s-triazine herbicides as sources of nitrogen. The choice of inoculum for these enrichments is important and often allows for successful enrichment after simple batch culture, but organisms containing several degradative reactions could be obtained only after selection in extended culture. Routine, specific determinations of all s-triazines (by HPLC) were essential throughout the work. Molar growth yields show complete mass balances for the utilization of s-triazines. Kinetic experiments indicate that specific degradation rates of s-triazines in growing cells are about 0.4 mkat/kg of protein. Characterised biochemical pathways consist of a series of hydrolytic cleavages of chloro-, amino-and alkylaminogroups from the s-triazine ring. Pathways con-
High‐Throughput Screening for Kinase Inhibitors (2005)

Following G protein-coupled receptors (GPCRs), protein kinases have become the second most important class of targets for drug discovery over the last 20 years. While only four kinase inhibitors have reached the market to date (Fasudil for rho-dependent kinase, Rapamycin for TOR, Gleevec for BCR-Abl, and Iressa for EGFR), many more are already in clinical development. A historical overview of kinase inhibitors was recently published by Cohen. [1] After the previous successes, protein kinases are now regarded as attractive, well-drugable targets, and the analysis of the human genome has yielded 518 protein kinases. [2] We can thus expect screening for protein kinase inhibitors to become even more important in the future. In this review we will focus on the early steps of drug discovery programs producing new lead compounds. We will guide the reader through efficient state-of-the-art assay development and high-throughput screening of large chemical libraries for protein kinase inhibitors.
Synthesis of Superparamagnetic Polymer−Ferrite Composites Using Surfactant Microstructures (1996)

Superparamagnetic microspheres are prepared by incorporating nanometer-sized iron oxide crystals into micron-sized phenolic polymer particles. The synthesis of ferrite particles is conducted in the structured environment of water-in-oil microemulsions (reversed micelles). This is followed by the enzymatic polymerization of p-ethylphenol. The polymer precipitates in spherical morphologies and during precipitation incorporates ferrite nanocrystals into the polymeric matrix. SQUID (superconducting quantum interference device) generated magnetic hysteresis loops exhibit zero remanence and coercivity for the ferrite−polymer composite at room temperature, indicating the superparamagnetic nature of the composite. At very low temperatures, hysteretic effects, nonzero remanence, and coercivity are seen. Spin glass behavior is apparent at low temperatures from dc magnetic susceptibility measurements. Thermal and isothermal remanent magnetization measurements confirm the existence of the spin glass state. The composites exhibit blocking temperatures in the range 12.0−27.0 K. TEM micrographs of sectioned composite particles show that the iron oxide component is uniformly distributed in the polymer matrix.
Winding through the WNT pathway during cellular development and demise. (2006)

In slightly over a period of twenty years, our comprehension of the cellular and molecular mechanisms that govern the Wnt signaling pathway continue to unfold. The Wnt proteins were initially implicated in viral carcinogenesis experiments associated with mammary tumors, but since this period investigations focusing on the Wnt pathways and their transmembrane receptors termed Frizzled have been advanced to demonstrate the critical nature of Wnt for the development of a variety of cell populations as well as the potential of the Wnt pathway to avert apoptotic injury. In particular, Wnt signaling plays a significant role in both the cardiovascular and nervous systems during embryonic cell patterning, proliferation, differentiation, and orientation. Furthermore, modulation of Wnt signaling under specific cellular influences can either promote or prevent the early and late stages of apoptotic cellular injury in neurons, endothelial cells, vascular smooth muscle cells, and cardiomyocytes. A number of downstream signal transduction pathways can mediate the biological response of the Wnt proteins that include Dishevelled, beta-catenin, intracellular calcium, protein kinase C, Akt, and glycogen synthase kinase-3beta. Interestingly, these cellular cascades of the Wnt-Frizzled pathways can participate in several neurodegenerative, vascular, and cardiac disorders and may be closely integrated with the function of trophic factors. Identification of the critical elements that modulate the Wnt-Frizzled signaling pathway should continue to unlock the potential of Wnt pathway for the development of new therapeutic options against neurodegenerative and vascular diseases.
A Randomized Double-Blinded Comparison of Phenylephrine and Ephedrine Infusion Combinations to Maintain Blood Pressure During Spinal Anesthesia for Cesarean Delivery: The Effects on Fetal Acid-Base Status and Hemodynamic Control (2008)

When varying combinations of phenylephrine and ephedrine were given by infusion to maintain arterial blood pressure during spinal anesthesia for cesarean delivery, as the proportion of phenylephrine decreased and the proportion of ephedrine increased, hemodynamic control was reduced and fetal acid-base status was less favorable. Combinations of phenylephrine and ephedrine appear to have no advantage compared with phenylephrine alone when administered by infusion for the prevention of hypotension associated with spinal anesthesia for cesarean delivery.
Monoclonal Antibody Against Human Fibronectin Which Inhibits Cell Attachment (1982)

Monoclonal antibodies have been prepared against both human and bovine fibronectin. Evidence is provided which indicates that nine different antigenic determinants are recognized by the ten antihuman fibronectin monoclonal antibodies isolated. One monoclonal antibody was identified that blocked fibronectin mediated cell attachment without interfering with fibronectin binding to collagen. Sensitive ELISA assays for fibronectins derived from 32 mammalian species have been developed with the monoclonal reagents characterized in this study.
Genetic analysis reveals cell type-specific regulation of receptor tyrosine kinase c-Kit by the protein tyrosine phosphatase SHP1. (1996)

Receptor protein tyrosine kinases (RTKs) transmit downstream signals via interactions with secondary signaling molecules containing SH2 domains. Although many SH2-phosphotyrosyl interactions have been defined in vitro, little is known about the physiological significance of specific RTK/SH2 interactions in vivo. Also, little is known about the mechanisms by which specific RTKs interact with and/or are regulated by specific protein tyrosine phosphatases (PTPs). To address such issue, we carried out a genetic analysis of the previously reported biochemical interaction between the RTK c-Kit, encoded at the W locus, and the SH2-containing non-transmembrane PTP SHP1, encoded at the motheaten (me) locus (1). Mice carrying a kinase-defective allele of c-Kit (Wv/+) were crossed with me/+ mice, which carry one effectively null allele of SHP1, and then backcrossed to generate all possible allelic combinations. Our results indicate strong intergenic complementation between these loci in hematopoietic progenitor cells. Compared to progenitors purified from normal mice, bone marrow progenitor cells (lin-) from me/me mice markedly hyper-proliferated in response to Kit ligand (KL). stimulation. Superimposition of the me/me genotype increased the number of one marrow-derived CFU-E from Wv/+ mice. Conversely, the presence of one or two copies of Wv decreased the number of macrophages and granulocytes in me/me lung, skin, peripheral blood and bone marrow, thereby decreasing the severity of the me/me phenotype. The decrease in dermal mast cells in Wv/Wv mice was rescued to levels found in Wv/+mice by superimposition of the me/me genotype. Surprisingly, however, the presence or absence of SHP1 had no effect on the proliferative response of bone marrow-derived cultured mast cells to KL or IL3 ex vivo. Nevertheless, the immediate-early response to KL stimulation, as measured by KL-induced tyrosyl phosphorylation, was substantially increased in mast cells from Wv/+:me/me compared to Wv/ +:+/+ mice, strongly suggesting that SHP1 directly dephosphorylates and regulates c-Kit. Taken together, our results establish that SHP1 negatively regulates signaling from c-Kit in vivo, but in a cell type-specific manner.
Principles of Local Drug Delivery to the Inner Ear (2009)

As more and more substances have been shown in preclinical studies to be capable of preventing damage to the inner ear from exposure to noise, ototoxic drugs, ischemia, infection, inflammation, mechanical trauma and other insults, it is becoming very important to develop feasible and safe methods for the targeted delivery of drugs to specific regions in the inner ear. Recently developed methods for sampling perilymph from the cochlea have overcome major technical problems that have distorted previous pharmacokinetic studies of the ear. These measurements show that drug distribution in perilymph is dominated by passive diffusion, resulting in large gradients along the cochlea when drugs are applied intratympanically. Therefore, in order to direct drugs to specific regions of the ear, a variety of delivery strategies are required. To target drugs to the basal cochlear turn and vestibular system while minimizing exposure of the apical cochlear turns, single one-shot intratympanic applications are effective. To increase the amount of drug reaching the apical cochlear turns, repeated intratympanic injections or controlled-release drug delivery systems, such as biodegradable biopolymers or catheters and pumps, are more effective. However, if the applied substance does not easily pass through the round window membrane, or if a more widespread distribution of drug in the ear is required, then intralabyrinthine injections of the substance may be required. Intralabyrinthine injection procedures, which are currently in development in animals, have not yet been proven safe enough for human use.
Syntenin, a PDZ protein that binds syndecan cytoplasmic domains (1997)

The syndecans are transmembrane proteoglycans that place structurally heterogeneous heparan sulfate chains at the cell surface and a highly conserved polypeptide in the cytoplasm. Their versatile heparan sulfate moieties support various processes of molecular recognition, signaling, and trafficking. Here we report the identification of a protein that binds to the cytoplasmic domains of the syndecans in yeast two-hybrid screens, surface plasmon resonance experiments, and ligand-overlay assays. This protein, syntenin, contains a tandem repeat of PDZ domains that reacts with the FYA C-terminal amino acid sequence of the syndecans. Recombinant enhanced green fluorescent protein (eGFP)-syntenin fusion proteins decorate the plasmamembrane and intracellular vesicles, where they colocalize and cosegregate with syndecans. Cells that overexpress eGFP-syntenin show numerous cell surface extensions, suggesting effects of syntenin on cytoskeleton-membrane organization. We propose that syntenin may function as an adaptor that couples syndecans to cytoskeletal proteins or cytosolic downstream signal-effectors.
The Changing View of High-Grade Serous Ovarian Cancer (2012)

The classification of epithelial ovarian cancer has been substantially revised, with an increased appreciation of the cellular origins and molecular aberrations of the different histotypes. Distinct patterns of signaling-pathway disruption are seen between and within histotypes. Large-scale genomic studies of high-grade serous cancer, the most common histotype, have identified novel molecular subtypes that are associated with distinct biology and clinical outcome. High-grade serous cancers are characterized by few driver point mutations but abundant DNA copy number aberrations. Inactivation of genes associated with DNA damage repair underlies responses to platinum and PARP inhibitors. Here we review these recent developments.
Assessing discreet packet-dropping attacks using nearest-neighbor and path-vector attribution (2007)

A Mobile Ad-Hoc Network (MANET) is considered with nodes that may act selfishly or maliciously by simply dropping data packets rather than forwarding them. We study a distributed route assessment (reputation) system for a MANET context in which nodes attribute a route’s performance to their nearest neighbors on the route. Also, attribution to all relaying nodes is studied for the case where path vectors are available, and blame for dropped packets is assigned to each node on the path. For the situation where there is sufficient mobility (“mixing”) within the domain, we show that these reputations converge to reveal the true relative dropping rates of the individual nodes. These results may be applicable to a more general category of peer-to-peer networks with sufficient route diversity.
Effect of Molecular Weight and Annealing of Poly(3‐hexylthiophene)s on the Performance of Organic Field‐Effect Transistors (2004)

Abstract The optical, structural, and electrical properties of thin layers made from poly(3‐hexylthiophene) (P3HT) samples of different molecular weights are presented. As reported in a previous paper by Kline et al., Adv. Mater. 2003 , 15 , 1519, the mobilities of these layers are a strong function of the molecular weight, with the largest mobility found for the largest molecular weight. Atomic force microscopy studies reveal a complex polycrystalline morphology which changes considerably upon annealing. X‐ray studies show the occurrence of a layered phase for all P3HT fractions, especially after annealing at 150 °C. However, there is no clear correlation between the differences in the transport properties and the data from structural investigations. In order to reveal the processes limiting the mobility in these layers, the transistor properties were investigated as a function of temperature. The mobility decreases continuously with increasing temperatures; with the same trend pronounced thermochromic effects of the P3HT films occur. Apparently, the polymer chains adopt a more twisted, disordered conformation at higher temperatures, leading to interchain transport barriers. We conclude that the backbone conformation of the majority of the bulk material rather than the crystallinity of the layer is the most crucial parameter controlling the charge transport in these P3HT layers. This interpretation is supported by the significant blue‐shift of the solid‐state absorption spectra with decreasing molecular weight, which is indicative of a larger distortion of the P3HT backbone in the low‐molecular weight P3HT layers.
Directness and liveness in the morphic user interface construction environment (1995)

Article Free Access Share on Directness and liveness in the morphic user interface construction environment Authors: John H. Maloney Apple Computer, Inc., 1 Infinite Loop, M/S 301-3E, Cupertino, CA Apple Computer, Inc., 1 Infinite Loop, M/S 301-3E, Cupertino, CAView Profile , Randall B. Smith Sun Microsystems Laboratories, 2550 Garcia Avenue, MTV 29-116 Mountain View, CA Sun Microsystems Laboratories, 2550 Garcia Avenue, MTV 29-116 Mountain View, CAView Profile Authors Info & Claims UIST '95: Proceedings of the 8th annual ACM symposium on User interface and software technologyDecember 1995 Pages 21–28https://doi.org/10.1145/215585.215636Published:01 December 1995Publication History 88citation904DownloadsMetricsTotal Citations88Total Downloads904Last 12 Months91Last 6 weeks8 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my AlertsNew Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteeReaderPDF
The glutamatergic basis of human alcoholism (1995)

A host of findings support the hypothesis that the unifying mechanism of action of ethanol in interference with glutamatergic neurotransmission, especially through the NMDA receptor. Alcoholism may be considered another member of the expanding family of glutamate-related neuropsychiatric disorders. These insights should increase understanding of the biologic vulnerabilities leading to ethanol abuse and dependence and aid development of more effective pharmacologic interventions.