gebhart/patrepeval huggingface dataset:
Requirement of Phosphatidylinositol 3-Kinase-Dependent Pathway and Src for Gas6-Axl Mitogenic and Survival Activities in NIH 3T3 Fibroblasts (1997)

Gas6 is a secreted protein previously identified as the ligand of the Axl receptor tyrosine kinase. We have shown that Gas6 is able to induce cell cycle reentry of serum-starved NIH 3T3 cells and to efficiently prevent apoptosis after complete growth factor removal, a survival effect uncoupled from Gas6-induced mitogenesis. Here we report that the mitogenic effect of Gas6 requires phosphatidylinositol 3-kinase (PI3K) activity since it is abrogated both by the specific inhibitor wortmannin and by overexpression of the dominant negative P13K p85 subunit. Consistently, Gas6 activates the P13K downstream targets S6K and Akt, whose activation is abrogated by addition of wortmannin. Moreover, rapamycin treatment blocks Gas6-induced entry into the S phase of serum-starved NIH 3T3 cells. We also demonstrate the requirement of Src tyrosine kinase for Gas6 signalling since stable or transient expression of a catalytically inactive form of Src significantly inhibited Gas6-stimulated entry into the S phase. Accordingly, Gas6 addition to serum-starved NIH 3T3 cells causes activation of the intrinsic Src kinase activity. When specifically analyzed in a survival assay, these elements were found to be required for the survival effect of Gas6. Taken together, the evidence presented here identifies elements involved in the Gas6 transduction pathway that are responsible for its antiapoptotic effect and suggests that Src is involved in the events regulating cell survival.
Colonic lavage solutions (1993)

Many patients dislike the taste of the oral gastrointestinal lavage solutions utilized prior to colonoscopy. Specifically, patients dislike the salty taste and the quantity of the polyethylene glycol-electrolyte solution that they are required to ingest. In an attempt to reduce the salty taste and potentially improve patient compliance and tolerance of the preparation, flavoring was added to the lavage solution. Fifty-six patients received standard or flavored polyethylene glycol-electrolyte lavage solution in random order prior to colonoscopy. In group I, lemon-flavored Colyte was compared with standard Colyte: 93% (25/27) of subjects preferred the flavored solution. In group II, standard Colyte was compared with lemon/lime-flavored Colyte, and 80% (8/10) of subjects preferred standard Colyte. In group III, lemon-flavored Colyte, standard Colyte, and NuLYTELY were compared. Ninety percent (17/19) of the subjects preferred lemon-flavored Colyte, 10% of the subjects preferred standard Colyte, and none of the subjects preferred NuLYTELY. Overall, patients preferred lemon-flavored solution over other solutions.
Role of Prodomain in Importin-mediated Nuclear Localization and Activation of Caspase-2 (2003)

Caspase-2 is unique among mammalian caspases because it localizes to the nucleus in a prodomain-dependent manner. The caspase-2 prodomain also regulates caspase-2 activity via a caspase recruitment domain that mediates oligomerization of procaspase-2 molecules and their subsequent autoactivation. In this study we sought to map specific functional regions in the caspase-2 prodomain that regulate its nuclear transport and also its activation. Our data indicate that caspase-2 contains a classical nuclear localization signal (NLS) at the C terminus of the prodomain which is recognized by the importin alpha/beta heterodimer. The mutation of a conserved Lys residue in the NLS abolishes nuclear localization of caspase-2 and binding to the importin alpha/beta heterodimer. Although caspase-2 is imported into the nucleus, mutants lacking the NLS were still capable of inducing apoptosis upon overexpression in transfected cells. We define a region in the prodomain that regulates the ability of caspase-2 to form dot- and filament-like structures when ectopically expressed, which in turn promotes cell killing. Our data provides a mechanism for caspase-2 nuclear import and demonstrate that association of procaspase-2 into higher order structures, rather than its nuclear localization, is required for caspase-2 activation and its ability to induce apoptosis.
Corruption of Innate Immunity by Bacterial Proteases (2008)

The innate immune system of the human body has developed numerous mechanisms to control endogenous and exogenous bacteria and thus prevent infections by these microorganisms. These mechanisms range from physical barriers such as the skin or mucosal epithelium to a sophisticated array of molecules and cells that function to suppress or prevent bacterial infection. Many bacteria express a variety of proteases, ranging from non-specific and powerful enzymes that degrade many proteins involved in innate immunity to proteases that are extremely precise and specific in their mode of action. Here we have assembled a comprehensive picture of how bacterial proteases affect the host's innate immune system to gain advantage and cause infection. This picture is far from being complete since the numbers of mechanisms utilized are as astonishing as they are diverse, ranging from degradation of molecules vital to innate immune mechanisms to subversion of the mechanisms to allow the bacterium to hide from the system or take advantage of it. It is vital that such mechanisms are elucidated to allow strategies to be developed to aid the innate immune system in controlling bacterial infections.
Assessment of Mitochondrial Function in Vivo With A Breath Test Utilizing α—Ketoisocaproic Acid (1989)

A breath test to assess hepatic mitochondrial function in vivo was evaluated in rats. Following the i.p. administration of [1-14C]-alpha-ketoisocaproic acid, 14CO2 exhalation reached a peak within 10 to 20 min and then declined exponentially, with a half-life of 14.3 min. Control animals exhaled 38.6% of the administered radioactivity within 1 hr. In functionally anhepatic animals, 14CO2 in breath amounted to 23% of that in control animals, indicating that alpha-ketoisocaproic acid decarboxylation reflects mainly hepatic mitochondrial function in vivo. Ethanol (3 gm per kg) significantly decreased alpha-ketoisocaproic acid decarboxylation (21.8% of the dose appearing in breath in 1 hr), probably due to the ethanol-induced shift in the NAD+:NADH ratio. In contrast, an uncoupler of mitochondrial respiration, sodium salicylate (375 mg per kg), increased the decarboxylation of alpha-ketoisocaproic acid (56.3% of the dose recovered as 14CO2 in 1 hr). Mitochondrial damage induced by 4-pentenoic acid decreased the decarboxylation of alpha-ketoisocaproic acid but did not affect the microsomal metabolism of antipyrine. The present data indicate that the alpha-ketoisocaproic acid breath test provides a noninvasive estimate of hepatic mitochondrial function in vivo which, when applied to man, might yield clinically useful information.
Inactivation of the gene encoding surface protein SspA in Streptococcus gordonii DL1 affects cell interactions with human salivary agglutinin and oral actinomyces (1993)

Cell surface protein SSP-5 in the oral bacterium Streptococcus gordonii M5 binds human salivary agglutinin in a Ca(2+)-dependent reaction (D.R. Demuth, E.E. Golub, and D. Malamud, J. Biol. Chem. 265:7120-7126, 1990). The region of the gene encoding an N-terminal segment of a related polypeptide (SspA) in S. gordonii DL1 (Challis) was isolated following polymerase chain reaction amplification of genomic DNA. The sspA gene in S. gordonii DL1 was insertionally inactivated by homologous recombination of the erythromycin resistance (Emr) determinant ermAM onto the streptococcal chromosome. The SspA polypeptide (apparent molecular mass, 210 kDa) was detected on Western blots (immunoblots) of spheroplast extracts and extracellular culture medium proteins from wild-type strain DL1 but was absent from Emr mutants. One SspA- mutant (designated OB220) was not altered in rate or extent of aggregation by whole saliva or parotid saliva but showed reduced aggregation in the presence of purified salivary agglutinin. Mutant bacteria were unaffected in their ability to adhere to hydroxylapatite beads coated with whole or parotid saliva and were unaltered in cell surface hydrophobicity. However, the SspA- strain OB220 was deficient in binding salivary agglutinin and in binding to six strains of Actinomyces naeslundii. Therefore, expression of SspA polypeptide in S. gordonii is associated with both agglutinin-dependent and agglutinin-independent aggregation and adherence reactions of streptococcal cells.
Comparison of Disintegrins with Limited Variation in the RGD Loop in Their Binding to Purified Integrins αIIbβ3, αVβ3 and α5β1 and in Cell Adhesion Inhibition (1994)

The inhibitory capacities of six different disintegrins and one related neurotoxin analogue for the binding of RGD-dependent integrins to either fibrinogen, vitronectin or fibronectin were compared in solid phase assays. Echistatin and flavoridin were the most active inhibitors for alpha V beta 3 and alpha 5 beta 1 integrins and moderately exceeded the activity of the natural protein ligands. The same disintegrins together with eristostatin, bitistatin and barbourin were also very potent inhibitors of fibrinogen binding to alpha IIb beta 3 integrin. For all three integrins, albolabrin showed the lowest affinity, but it still clearly exceeded that of synthetic GRGDS. However, assay conditions may determine these relative affinities, as shown for the alpha IIb beta 3 and alpha V beta 3 integrins when used either in immobilized or soluble form. For alpha IIb beta 3, however, a close correlation was found between KD values determined in platelet binding assays and the concentrations required for half maximal inhibition of three disintegrins. The inhibiting capacity of disintegrins in assays with purified integrins also correlated reasonably well with their inhibition of cell attachment to RGD-dependent protein substrates. However, sequence differences in the RGD loops of the various disintegrins may not fully account for the 20-100-fold difference in their binding capacities. This was particularly evident for echistatin and albolabrin, which differ in this region only by two conservative substitutions but have considerably different inhibitory activities. More remote regions of the disintegrins and alignment of disulfide bridges are therefore likely to contribute to their affinity and selectivity.
Deep Interactive Object Selection (2016)

Interactive object selection is a very important research problem and has many applications. Previous algorithms require substantial user interactions to estimate the foreground and background distributions. In this paper, we present a novel deep-learning-based algorithm which has much better understanding of objectness and can reduce user interactions to just a few clicks. Our algorithm transforms user-provided positive and negative clicks into two Euclidean distance maps which are then concatenated with the RGB channels of images to compose (image, user interactions) pairs. We generate many of such pairs by combining several random sampling strategies to model users' click patterns and use them to finetune deep Fully Convolutional Networks (FCNs). Finally the output probability maps of our FCN-8s model is integrated with graph cut optimization to refine the boundary segments. Our model is trained on the PASCAL segmentation dataset and evaluated on other datasets with different object classes. Experimental results on both seen and unseen objects demonstrate that our algorithm has a good generalization ability and is superior to all existing interactive object selection approaches.
PDCD10/CCM3 Acts Downstream of γ-Protocadherins to Regulate Neuronal Survival (2010)

γ-Protocadherins (PCDH-γ) regulate neuronal survival in the vertebrate central nervous system. The molecular mechanisms of how PCDH-γ mediates this function are still not understood. In this study, we show that through their common cytoplasmic domain, different PCDH-γ isoforms interact with an intracellular adaptor protein named PDCD10 (programmed cell death 10). PDCD10 is also known as CCM3, a causative genetic defect for cerebral cavernous malformations in humans. Using RNAi-mediated knockdown, we demonstrate that PDCD10 is required for the occurrence of apoptosis upon PCDH-γ depletion in developing chicken spinal neurons. Moreover, overexpression of PDCD10 is sufficient to induce neuronal apoptosis. Taken together, our data reveal a novel function for PDCD10/CCM3, acting as a critical regulator of neuronal survival during development.
PND-1186 FAK inhibitor selectively promotes tumore cell apoptosis in three-dimensional environments (2010)

Commentary to:PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environmentsIsabelle Tanjoni, Colin Walsh, Sean Uryu, Alok Tomar, Ju-Ock Nam, Ainhoa Mielgo, Ssang-Taek Lim, Congxin Liang, Marcel Koenig, Neela Patel, Cheni Kwok, Gerald McMahon, Dwayne G. Stupack and David D. Schlaepfer
Connecting Solubility, Equilibrium, and Periodicity in a Green, Inquiry Experiment for the General Chemistry Laboratory (2008)

We present a novel first-year chemistry laboratory experiment that connects solubility, equilibrium, and chemical periodicity concepts. It employs a unique format that asks students to replicate experiments described in different sample lab reports, each lacking some essential information, rather than follow a scripted procedure. This structure is designed, based on research findings on the science of learning, to promote development of students' experimental design and data analysis skills as well as their understanding of the importance and essential qualities of written and verbal communication between scientists. The experiment begins with titration of saturated solutions of magnesium, calcium, and strontium hydroxides followed by the calculation of the solubility product of each compound. Students use their results to determine a periodic trend in the solubility of the group 2 compounds they titrated, apply the trend to predict the solubility of other, toxic group 2 hydroxides, and examine the value of the experiment within the context of a green chemistry philosophy.
Role of Translocation in the Activation and Function of Protein Kinase B (1997)

We have investigated the role of subcellular localization in the regulation of protein kinase B (PKB) activation. The myristoylation/palmitylation motif from the Lck tyrosine kinase was attached to the N terminus of protein kinase B to alter its subcellular location. Myristoylated/palmitylated (m/p)-PKBalpha was associated with the plasma membrane of transfected cells, whereas the wild-type kinase was mostly cytosolic. The activity of m/p-PKBalpha was 60-fold higher compared with the unstimulated wild-type enzyme, and could not be stimulated further by growth factors or phosphatase inhibitors. In vivo 32P labeling and mutagenesis demonstrated that m/p-PKBalpha activity was due to phosphorylation on Thr308 and Ser473, that are normally induced on PKB following stimulation of the cells with insulin or insulin-like growth factor-1 (IGF-1). A dominant negative form of phosphoinositide 3-kinase (PI3-K) did not affect m/p-PKBalpha activity. The pleckstrin homology (PH) domain of m/p-PKBalpha was not required for its activation or phosphorylation on Thr308 and Ser473, suggesting that this domain may serve as a membrane-targeting module. Consistent with this view, PKBalpha was translocated to the plasma membrane within minutes after stimulation with IGF-1. This translocation required the PH domain and was sensitive to wortmannin. Our results indicate that PI3-K activity is required for translocation of PKB to the plasma membrane, where its activation occurs through phosphorylation of the same sites that are induced by insulin or IGF-1. Following activation the kinase detached from the membrane and translocated to the nucleus.
Targeting toll‐like receptors for drug development: a summary of commercial approaches (2007)

Toll-like receptors (TLRs) play a fundamental role in recognizing infectious and noxious agents as well as products of tissue damage. They are capable of initiating both protective and damaging inflammatory and immune responses. Several biotechnology and pharmaceutical companies have programmes to develop new drugs that are either: agonists of TLRs to enhance immune responses against tumours and infectious agents, or to correct allergic responses; or antagonists designed to reduce inflammation due to infection or autoimmune disease. This article reviews the commercial approaches being undertaken to develop new TLR drugs.
Stimulation of Myogenic Differentiation by a Neuregulin, Glial Growth Factor 2 (1996)

It has long been known that nerves stimulate growth and maintenance of skeletal muscles in ways not dependent on physical contacts, but numerous attempts to identify and characterize the myotrophic agent(s) secreted by nerves have been unsuccessful. We here suggest that products of the neuregulin gene may be these agents. The neuregulins are a family of proteins made by alternative splicing of a single transcript to give as many as 15 protein products. One member of this family, glial growth factor 2 (rhGGF2) is a very potent stimulator of myogenesis in L6A1 myoblasts, giving a maximal stimulation of cell fusion and creatine kinase elevation at a concentration of 1 ng/ml (18 pM). The stimulation of myogenesis is not rapid, but it is prolonged, continuing over a period of at least 6 days. The effects of rhGGF2 are additive with those of insulin-like growth factor I (IGF-I) or its analog R3-IGF-I, suggesting that the actions of these two myotrophic agents differ in at least one rate-limiting step. We have observed one possible difference; unlike the IGFs, rhGGF2 does not induce elevation of the steady state level of myogenin mRNA.
The TLR-7 Agonist, Imiquimod, Enhances Dendritic Cell Survival and Promotes Tumor Antigen-Specific T Cell Priming: Relation to Central Nervous System Antitumor Immunity (2006)

Immunotherapy represents an appealing option to specifically target CNS tumors using the immune system. In this report, we tested whether adjunctive treatment with the TLR-7 agonist imiquimod could augment antitumor immune responsiveness in CNS tumor-bearing mice treated with human gp100 + tyrosine-related protein-2 melanoma-associated Ag peptide-pulsed dendritic cell (DC) vaccination. Treatment of mice with 5% imiquimod resulted in synergistic reduction in CNS tumor growth compared with melanoma-associated Ag-pulsed DC vaccination alone. Continuous imiquimod administration in CNS tumor-bearing mice, however, was associated with the appearance of robust innate immune cell infiltration and hemorrhage into the brain and the tumor. To understand the immunological mechanisms by which imiquimod augmented antitumor immunity, we tested whether imiquimod treatment enhanced DC function or the priming of tumor-specific CD8+ T cells in vivo. With bioluminescent, in vivo imaging, we determined that imiquimod dramatically enhanced both the persistence and trafficking of DCs into the draining lymph nodes after vaccination. We additionally demonstrated that imiquimod administration significantly increased the accumulation of tumor-specific CD8+ T cells in the spleen and draining lymph nodes after DC vaccination. The results suggest that imiquimod positively influences DC trafficking and the priming of tumor-specific CD8+ T cells. However, inflammatory responses induced in the brain by TLR signaling must also take into account the local microenvironment in the context of antitumor immunity to induce clinical benefit. Nevertheless, immunotherapeutic targeting of malignant CNS tumors may be enhanced by the administration of the innate immune response modifier imiquimod.
Lattice‐Boltzmann studies of immiscible two‐phase flow through porous media (1993)

Using a recently introduced numerical technique known as a lattice‐Boltzmann method, we numerically investigate immiscible two‐phase flow in a three‐dimensional microscopic model of a porous medium and attempt to establish the form of the macroscopic flow law. We observe that the conventional linear description of the flow is applicable for high levels of forcing when the relative effects of capillary forces are small. However, at low levels of forcing capillary effects become important and the flow law becomes nonlinear. By constructing a two‐dimensional phase diagram in the parameter space of nonwetting saturation and dimensionless forcing, we delineate the various regions of linearity and nonlinearity and attempt to explain the underlying physical mechanisms that create these regions. In particular, we show that the appearance of percolated, throughgoing flow paths depends not only on the relative concentrations of the two fluids but also on a dimensionless number that represents the ratio of the applied force to the force necessary for nonwetting fluid to fully penetrate through the porous medium. Finally, we fit a linear model to our simulation data in the high‐forcing regions of the system and observe that an Onsager reciprocity holds for the viscous coupling of the two fluids.
The Use of Polarization Filters to Detect the Edge of the Descemet’s Stripping Automated Endothelial Keratoplasty(DSAEK) Graft (2009)

This simple system with polarization filters was effective in clear visualization of the flap edge during DSAEK tissue preparation. These features may significantly enhance safety of various surgical procedures, in addition to DSAEK tissue preparation.
Development of a new poly(ethylene glycol)‐graft‐poly(D,L‐lactic acid) as potential drug carriers (2008)

A new poly(ethylene glycol) (PEG)-modified poly(D,L-lactic acid) (PLA) was synthesized by grafting maleic anhydride onto PLA and subsequently amidating with O,O'-bis-(2-aminopropyl) polypropylene glycol-block-polyethylene oxide-block-polypropylene glycol (H2N-PEG-NH2, Mw: 600). Its structure was confirmed by FTIR, DSC, 1H NMR, GPC, and ninhydrin test. The polymer is more hydrophilic compared with PLA according to contact angle tests, and is degradable as determined from its pH and mass changes during degradation. The polymer shows a 62.7% decrease in BSA absorption compared with PLA when dried in air, and a 82.76% decrease when dried under 65% humidity, as measured by fluorospectrophotometry. The polymer promotes adhesion and proliferation of osteoblasts, determined by MTT assay. With this new polymer, spherical nanoscale aggregates encapsulated with or without hydrophilic dye are formed spontaneously in water, visualized by inverted microscope and AFM. The particle size is concentration dependent as confirmed by dynamic light scattering, and its critical micelle concentration was 1.124 microg/mL as determined by a fluorescence method. The good hydrophilicity, degradability, cellular compatibility, protein-resistance, self-aggregation, and reactivity of the polymer may lead to its potential applications in drug delivery.