gebhart/patrepeval huggingface dataset:
Receptor for urokinase is present in tumor-associated macrophages in ductal breast carcinoma. (1993)

Histological samples from 60 invasive ductal breast carcinomas were investigated for immunoreactivity for the receptor for urokinase-type plasminogen activator (uPAR) with the use of two monoclonal antibodies recognizing different epitopes. In 51 cases, uPAR immunoreactivity was observed, and in 49 of these specimens, a population of periductal tissue macrophages showed pronounced uPAR immunoreactivity in areas with infiltrating and intraductal carcinoma. In the 2 remaining positive specimens no stromal immunoreactivity was seen. The carcinoma cells were found to contain uPAR immunoreactivity in 8 of the 51 positive cases, including the two specimens that did not show stromal immunostaining. Immunoactivity was not found in the epithelial cells of carcinoma in situ components occasionally seen in the specimens, but stromal macrophage-like cells which had invaded such lesions were positive. In most specimens a subpopulation of tissue neutrophils was also positive. Normally appearing epithelium in all specimens investigated was negative, and no other tissue elements were stained in any of the samples. Ten samples of normal female breast tissue were negative. This is the first report on the immunohistochemical distribution of uPAR in human cancer tissue, and the results provide evidence for a role of the urokinase receptor in providing tissue macrophages a means of directing proteolysis at sites of breast cancer invasion. This macrophage-mediated proteolytic activity is suggested to be involved in the invasion and subsequent distant spreading of this malignancy.
Two Isoforms of the Prostaglandin E Receptor EP3 Subtype Different in Agonist-independent Constitutive Activity (1996)

We previously identified two isoforms of the mouse prostaglandin E receptor EP3 subtype, EP3 alpha and EP3 beta, with different carboxyl-terminal tails, produced through alternative splicing and showing different efficiency in inhibition of adenylate cyclase (Sugimoto, Y., Negishi, M., Hayashi, Y., Namba, T., Honda, A., Watabe, A., Hirata, M., Narumiya, S., and Ichikawa, A. (1993) J. Biol. Chem. 268, 2712-2718). To assess the role of the carboxyl-terminal tails in the G protein coupling properties of the EP3 receptor, we examined the Gi activities of EP3 alpha, EP3 beta, and the mutant receptor, in which the carboxyl-terminal tail was truncated at the splicing site. The EP3 alpha receptor showed marked agonist-independent constitutive inhibition of adenylate cyclase, while EP3 beta receptor had no agonist-independent inhibition. On the other hand, the truncated receptor showed only agonist-independent constitutive inhibition. The constitutive activity of these receptors on the stimulation of GTPase activity of Gi was also observed. Thus, alternative splicing produced two isoforms with different carboxyl-terminal tails and with different constitutive activity, and the truncation of the carboxyl-terminal tail caused full constitutive activity.
Platelet function and Isoprostane biology. Should Isoprostanes be the newest member of the Orphan-ligand family? (2010)

While there have been many reports investigating the biological activity and signaling mechanisms of isoprostanes, their role in biology, particularly in platelets, appears to still be underestimated. Moreover, whether these lipids have their own receptors is still debated, despite multiple reports that discrete receptors for isoprostane do exist on platelets, vascular tissues, amongst others. This paper provides a review of the important literature of isoprostanes and provides reasoning that isoprostanes should be classified as orphan ligands until their receptor(s) is/are identified.
GAL4 Interacts with TATA-Binding Protein and Coactivators (1995)

A major goal in understanding eukaryotic gene regulation is to identify the target(s) of transcriptional activators. Efforts to date have pointed to various candidates. Here we show that a 34-amino-acid peptide from the carboxy terminus of GAL4 is a strong activation domain (AD) and retains at least four proteins from a crude extract: the negative regulator GAL80, the TATA-binding protein (TBP), and the putative coactivators SUG1 and ADA2. TFIIB was not retained. Concentrating on TBP, we demonstrate in in vitro binding assays that its interaction with the AD is specific, direct, and salt stable up to at least 1.6 M NaCl. The effects of mutations in the GAL4 AD on transcriptional activation in vivo correlate with their affinities to TBP. A point mutation (L114K) in yeast TBP, which has been shown to compromise the mutant protein in both binding to the VP16 AD domain and activated transcription in vitro, reduces the affinity to the GAL4 AD to the same degree as to the VP16 AD. This suggests that these two prototypic activators make similar contacts with TBP.
Inactivation of factor VIII coagulant activity by two different types of human antibodies (1982)

Human antibodies that inactivate factor VIII procoagulant activity (VIII:C) are heterogeneous in their kinetic properties. We report there here the properties of four type I and four type II antibodies classified according to Biggs et al. Type I antibodies have second-order inactivation kinetics and completely destroy VIII:C when present in high concentration; type II antibodies have more complex kinetics and do not completely inactivate VIII:C even when tested undiluted. The latter properties correspond to the in vivo finding in some patients that there is detectable VIII:C, even though there is also a significant inhibitor titer. It has been suggested that the antibody-antigen complex in these patients retains some VIII:C activity. This is unlikely, however, since protein-A-Sepharose (PAS) did not adsorb any VIII:C activity from mixtures of type II antibodies with normal human plasma. An alternate possibility, reduced VIII:C inactivation due to a steric effect the factor-VIII-related protein (VIIIR, von Willebrand factor), appears to be a more important factor, since three of four type II antibodies had inactivating properties like type I antibodies when they were tested with separated VIII:C instead of plasma. Although the fourth type II antibody did not completely inactivate separated VIII:C the residual coagulant activity was adsorbed from this mixture by PAS. These data indicate that type II anti-VIII:C react with different antigenic determinants than type I antibodies and that these determinants are partially blocked in the factor VIII complex by VIIIR.
A programmable Cas9-serine recombinase fusion protein that operates on DNA sequences in mammalian cells (2016)

We describe the development of 'recCas9', an RNA-programmed small serine recombinase that functions in mammalian cells. We fused a catalytically inactive dCas9 to the catalytic domain of Gin recombinase using an optimized fusion architecture. The resulting recCas9 system recombines DNA sites containing a minimal recombinase core site flanked by guide RNA-specified sequences. We show that these recombinases can operate on DNA sites in mammalian cells identical to genomic loci naturally found in the human genome in a manner that is dependent on the guide RNA sequences. DNA sequencing reveals that recCas9 catalyzes guide RNA-dependent recombination in human cells with an efficiency as high as 32% on plasmid substrates. Finally, we demonstrate that recCas9 expressed in human cells can catalyze in situ deletion between two genomic sites. Because recCas9 directly catalyzes recombination, it generates virtually no detectable indels or other stochastic DNA modification products. This work represents a step toward programmable, scarless genome editing in unmodified cells that is independent of endogenous cellular machinery or cell state. Current and future generations of recCas9 may facilitate targeted agricultural breeding, or the study and treatment of human genetic diseases.
The Power Behind the Throne: Senescence and the Hallmarks of Cancer (2017)

Cellular senescence is a state of stable proliferative arrest triggered by various stimuli, including oncogenic and other cellular stress. Senescent cells are highly metabolically active and have diverse and profound nonautonomous effects through the senescence-associated secretory phenotype (SASP). It has become increasingly evident that senescent cells can have tumour suppressive or pro-oncogenic effects on adjacent cancer cells and other players in the tumor microenvironment such as the stroma, vasculature, and immune system. Thus, the last decade or so has witnessed a huge leap forward in our understanding of the biology of senescence, promoting it from an autonomous tumor suppressor to a complex, dynamic, and interactive phenotype. It is perhaps not a coincidence that the concept of the “hallmarks of cancer” has also evolved during this period, with the latest iteration ( Hanahan &amp; Weinberg 2011 ) focusing more on the microenvironment. Here, we suggest that cellular senescence could underpin the biology of many of the hallmarks of cancer, making it the true power behind the throne.
patched Overexpression Causes Loss of wingless Expression in Drosophila Embryos (1994)

The patched (ptc) segment polarity gene of Drosophila encodes a transmembrane protein involved in cell signaling that establishes pattern within the segment. In the posterior half of the parasegment Patched protein represses transcription of the wingless (wg) gene by an unknown mechanism. In the most posterior row of cells in each parasegment this repression is neutralized by a signal possibly carried by the product of the hedgehog gene, allowing wg expression. High levels of Patched expression might therefore overcome the repression and repress wg in all cells. Here we use a heat shock-inducible promoter to transiently express high levels of Patched in all cells. A single pulse of Patched transgene expression has little or no effect on the segmental pattern, as has been previously reported. Repeated pulses of Patched production drastically alter the segment pattern to mimic embryos lacking one of the wg class of segment polarity genes. We observe repression of wg and gooseberry (a wg class gene) transcription in the germband ectoderm but not in the head. Expression of two other segment polarity genes, engrailed and cubitus interruptus, is unaffected. Thus excess Patched is capable of overcoming the neutralizing signal.
Methylation-sensitive high resolution melting (MS-HRM): a new approach for sensitive and high-throughput assessment of methylation (2007)

In this article, we show that high resolution melting analysis (HRM) is a sensitive and specific method for the detection of methylation. Methylated DNA and unmethylated DNA acquire different sequences after bisulphite treatment resulting in PCR products with markedly different melting profiles. We used PCR to amplify both methylated and unmethylated sequences and assessed HRM for the determination of the methylation status of the MGMT promoter region. Reconstruction experiments showed that MGMT methylation could be detected at levels as low as 0.1%. Moreover, MS-HRM allows for estimation of the methylation level by comparing the melting profiles of unknown PCR products to the melting profiles of PCR products derived from standards with a known unmethylated to methylated template ratio. We used MS-HRM for the analysis of eight cell lines of known methylation status and a panel of colorectal cancer specimens. The simplicity and high reproducibility of the MS-HRM protocol makes MS-HRM the method of choice for methylation assessment in many diagnostic and research applications.
Effect of the delta subunit on assembly and proton permeability of the F0 proton channel of Escherichia coli F1F0 ATPase (1991)

During the assembly of the Escherichia coli proton-translocating ATPase, the subunits of F1 interact with F0 to increase the proton permeability of the transmembrane proton channel. We tested the involvement of the delta subunit in this process by partially and completely deleting uncH (delta subunit) from a plasmid carrying the genes for the F0 subunits and delta and testing the effects of those F0 plasmids on the growth of unc+ and unc mutant E. coli strains. We found that the delta subunit was required for inhibition of growth of unc+ cells. We also tested membranes isolated from unc-deleted cells containing F0 plasmids for F1-binding ability. In unc-deleted cells, these plasmids produced F0 in amounts comparable to those found in normal unc+ E. coli cells, while having only small effects on cell growth. These studies demonstrate that the delta subunit plays an important role in opening the F0 proton channel but that it does not serve as a temporary plug of F0 during assembly, as had been previously speculated (S. Pati and W. S. A. Brusilow, J. Biol. Chem. 264:2640-2644, 1989).
Suspension Plasma Spraying of Nanostructured WC-12 Co Coatings (2006)

Abstract Nanostructured WC-12%Co coatings were deposited by suspension plasma spraying of submicron feedstock powders, using an internal injection plasma torch. The liquid carrier employed in this approach allows for controlled injection of much finer particles than in conventional thermal spraying, leading to thin coatings with a fine surface finish. A PEI (polyethylene-imine) dispersant was used to stabilize the colloidal suspension in an ethanol carrier. In-flight particle states were measured for a number of operating conditions of varying plasma gas flow rates, feed rates and standoff distances, and related to the resulting microstructure, phase composition (EDS, SEM, XRD) and Vickers hardness. High in-flight particle velocities, in excess of 800 m/sec, were generated, leading to dense coatings. It was observed that the coating quality was generally compromised by the high temperature and reactivity of the small particles. To compensate for this shortcoming, the suspension feed rate was adjusted, thereby varying the thermal load on the plasma. Results showed that a slightly larger agglomerate size, in conjunction with low particle jet temperatures, could somewhat limit the decomposition of WC into brittle W2C/W3C and amorphous cobalt containing binder phases.
Clinical safety of ranibizumab in age-related macular degeneration (2009)

Although further studies to investigate the risk of stroke with ranibizumab therapy are required, repeated intravitreal ranibizumab was well tolerated and not associated with clinically significant safety risks during up to 2 years of treatment.
The molecular biology of Huntington's disease (2001)

Although many interesting findings have accumulated from studies of HD and other polyglutamine diseases, there remain many unresolved issues pertaining to the exact roles of intranuclear inclusions and protein aggregates, the mechanisms of selective neuronal death and delayed onset of illness. Further knowledge in these areas will inspire the development of novel therapeutic strategies.
Hyperglycemia and downregulation of caveolin‐1 enhance neuregulin‐induced demyelination (2008)

Neuregulins (NRGs) are growth factors which bind to Erb receptor tyrosine kinases that localize to Schwann cells (SCs). Although NRGs can promote cell survival, mitogenesis, and myelination in undifferentiated SCs, they also induce demyelination of myelinated co-cultures of SCs and dorsal root ganglion (DRG) neurons. We have shown previously that Erb B2 activity increased in premyelinating SCs in response to hyperglycemia, and that this correlated with the downregulation of the protein caveolin-1 (Cav-1). As myelinated SCs undergo substantial degeneration in diabetic neuropathy, we used myelinated SC/DRG neuron co-cultures to determine if hyperglycemia and changes in Cav-1 expression could enhance NRG-induced demyelination. In basal glucose, NRG1 caused a 2.4-fold increase in the number of damaged myelin segments. This damage reached 3.8-fold under hyperglycemic conditions, and was also associated with a robust decrease in the expression of Cav-1 and compact myelin proteins. The loss of Cav-1 and compact myelin proteins following hyperglycemia and NRG treatment was not due to neuronal loss, since the axons remained intact and there was no loss of PGP 9.5, an axonal marker protein. To examine if changes in Cav-1 were sufficient to alter the extent of NRG-induced demyelination, SC/DRG neurons co-cultures were infected with antisense or dominant-negative Cav-1(P132L) adenoviruses. Either antisense-mediated downregulation or mis-localization of endogenous Cav-1 by Cav-1(P132L) resulted in a 1.5- to 2.4-fold increase in NRG-induced degeneration compared to that present in control cultures. These data support that hyperglycemia and changes in Cav-1 are sufficient to sensitize myelinated SC/DRG co-cultures to NRG-induced demyelination.
Favorable prognosis of renal cell carcinoma with increased expression of chemokines associated with a Th1‐type immune response (2006)

The potential role of chemokines in clinical tumors remains poorly understood. Recent investigations have shown the differential expression of chemokine receptors on lymphocytes mediating Th1- and Th2-type immune responses. We examined Th1- and Th2-associated cytokines and chemokines, as well as the expression of their receptors in tumor-infiltrating lymphocytes in renal cell carcinoma (RCC). Sixty-seven patients with sporadic RCC were analyzed for the expression of Th1- and Th2-associated genes using real-time polymerase chain reaction. Tumor infiltration by CXC chemokine receptor 3 (CXCR3)-positive and CC chemokine receptor 5 (CCR5)-positive cells was detected by immunohistochemistry and by flow cytometry. The expression of Th1-associated genes was significantly increased in tumors compared to normal kidney tissues. The expression of interferon-gamma correlated positively with that of Th1 chemokines. Tumors expressing higher Th1 chemokines did not recur after curative surgery. Multivariate analysis showed that increased monokine induced by interferon (IFN)-gamma (MIG) expression was an independent favorable prognostic factor. Immunohistochemistry showed that the degree of CXCR3-positive cell infiltration significantly correlated with IFN-gamma inducible protein 10, MIG and IFN-gamma-inducible T cell a chemoattractant expression (I-TAC). Flow cytometric analysis showed increased expression of CXCR3 and CCR5 in tumor-infiltrating T lymphocytes compared to that in peripheral blood T cells. These results suggest that upregulation of the Th1-type immune response in RCC tumors with a favorable prognosis may be mediated by Th1-associated chemokines. Integrity of the Th1-type immune response seems to be required for tumor regression, suggesting that detection and correction of a defect in the Th1-type response cascade would thus be one of the main targets for tailor-made immunotherapy and gene therapy in RCC.
Separable Learning Systems in the Macaque Brain and the Role of Orbitofrontal Cortex in Contingent Learning (2010)

Orbitofrontal cortex (OFC) is widely held to be critical for flexibility in decision-making when established choice values change. OFC's role in such decision making was investigated in macaques performing dynamically changing three-armed bandit tasks. After selective OFC lesions, animals were impaired at discovering the identity of the highest value stimulus following reversals. However, this was not caused either by diminished behavioral flexibility or by insensitivity to reinforcement changes, but instead by paradoxical increases in switching between all stimuli. This pattern of choice behavior could be explained by a causal role for OFC in appropriate contingent learning, the process by which causal responsibility for a particular reward is assigned to a particular choice. After OFC lesions, animals' choice behavior no longer reflected the history of precise conjoint relationships between particular choices and particular rewards. Nonetheless, OFC-lesioned animals could still approximate choice-outcome associations using a recency-weighted history of choices and rewards.
A fully automated immunoassay from whole blood on a disc (2009)

A portable, disc-based, and fully automated enzyme-linked immuno-sorbent assay (ELISA) system is developed to test infectious diseases from whole blood. The innovative laser irradiated ferrowax microvalves and centrifugal microfluidics were utilized for the full integration of microbead-based suspension ELISA assays on a disc starting from whole blood. The concentrations of the antigen and the antibody of Hepatitis B virus (HBV), HBsAg and Anti-HBs respectively, were measured using the lab-on-a-disc (LOD). All the necessary reagents are preloaded on the disc and the total process of the plasma separation, incubation with target specific antigen or antibody coated microbeads, multiple steps of washing, enzyme reaction with substrates, and the absorbance detection could be finished within 30 minutes. Compared to the conventional ELISA, the operation time was dramatically reduced from over 2 hours to less than 30 minutes while the limit of detection was kept similar; e.g. the limit of detection of Anti-HBs tests were 8.6 mIU mL(-1) and 10 mIU mL(-1) for the disc-based and the conventional ELISA respectively.
Activation of factor VIII by factor IXa (1982)

Thrombin causes an increase in factor VIII coagulant (VIII:C) activity, which is followed by a decay of VIII:C activity to below baseline levels. It has been suggested that a similar interaction of trace amounts of thrombin and factor VIII is a necessary prerequisite before factor VIII can participate in the coagulation cascade. In the current study, factor IXa, a serine protease with structural similarities to thrombin, is shown to cause an increase and subsequent fall in VIII:C in a manner qualitatively similar to the reaction with thrombin. The reaction is inhibited by a human inhibitor to factor IX and the interaction appears to involve only VIII:C, since factor-VIII-related protein (VIII:RP) is not changed on polyacrylamide gel electrophoresis (PAGE) or radioimmunoassay during the reaction. Phospholipid increases the activation of factor VIII by factor IXa, and high concentrations of diisopropylfluorophosphate and hirudin inhibit the reaction. The physiologic significance of the interaction of factor IXa with factor VIII is not entirely clear since the concentration of factor IXa needed for activation is much greater than the concentration of thrombin required for similar activation of factor VIII. Factor IXa is most likely to play a role in the intrinsic cascade acting as an initial activator of factor VIII, since factor IXa precedes thrombin in this clotting sequence. In addition, factor IXa may be important wherever relatively high local concentrations of factor IXa and factor VIII occur, particularly in the presence of phospholipid, which may serve to localize the coagulation factors.
Automated Essay Scoring in Innovative Assessments of Writing from Sources (2013)

This study examined automated essay scoring for experimental tests of writing from sources. These tests (part of the CBAL research initiative at ETS) embed writing tasks within a scenario in which students read and respond to sources. Two large-scale pilots are reported: One was administered in 2009, in which four writing assessments were piloted, and one was administered in 2011, in which two writing assessments and two reading assessments were administered. Two different rubrics were applied by human raters to each prompt: a general rubric intended to measure only those skills for which automated essay scoring provides relatively direct measurement, and a genre-specific rubric focusing on specific skills such as argumentation and literary analysis. An automated scoring engine (e-rater) was trained on part of the 2009 dataset, and cross-validated against the remaining 2009 dataset and all the 2011 data. The results indicated that automated scoring can achieve operationally acceptable levels of accuracy in this context. However, differentiation between the general rubric and the genre-specific rubric reinforces the need to achieve full construct coverage by supplementing automated scoring with additional sources of evidence.