gebhart/patrepeval huggingface dataset:
FAK signaling in human cancer as a target for therapeutics (2014)

Focal adhesion kinase (FAK) is a key regulator of growth factor receptor- and integrin-mediated signals, governing fundamental processes in normal and cancer cells through its kinase activity and scaffolding function. Increased FAK expression and activity occurs in primary and metastatic cancers of many tissue origins, and is often associated with poor clinical outcome, highlighting FAK as a potential determinant of tumor development and metastasis. Indeed, data from cell culture and animal models of cancer provide strong lines of evidence that FAK promotes malignancy by regulating tumorigenic and metastatic potential through highly-coordinated signaling networks that orchestrate a diverse range of cellular processes, such as cell survival, proliferation, migration, invasion, epithelial-mesenchymal transition, angiogenesis and regulation of cancer stem cell activities. Such an integral role in governing malignant characteristics indicates that FAK represents a potential target for cancer therapeutics. While pharmacologic targeting of FAK scaffold function is still at an early stage of development, a number of small molecule-based FAK tyrosine kinase inhibitors are currently undergoing pre-clinical and clinical testing. In particular, PF-00562271, VS-4718 and VS-6063 show promising clinical activities in patients with selected solid cancers. Clinical testing of rationally designed FAK-targeting agents with implementation of predictive response biomarkers, such as merlin deficiency for VS-4718 in mesothelioma, may help improve clinical outcome for cancer patients. In this article, we have reviewed the current knowledge regarding FAK signaling in human cancer, and recent developments in the generation and clinical application of FAK-targeting pharmacologic agents.
Antigen-Specific B Cell Memory (2000)

The mechanisms that regulate B cell memory and the rapid recall response to antigen remain poorly defined. This study focuses on the rapid expression of B cell memory upon antigen recall in vivo, and the replenishment of quiescent B cell memory that follows. Based on expression of CD138 and B220, we reveal a unique and major subtype of antigen-specific memory B cells (B220(-)CD138(-)) that are distinct from antibody-secreting B cells (B220(+/)-CD138(+)) and B220(+)CD138(-) memory B cells. These nonsecreting somatically mutated B220(-) memory responders rapidly dominate the splenic response and comprise >95% of antigen-specific memory B cells that migrate to the bone marrow. By day 42 after recall, the predominant quiescent memory B cell population in the spleen (75-85%) and the bone marrow (>95%) expresses the B220(-) phenotype. Upon adoptive transfer, B220(-) memory B cells proliferate to a lesser degree but produce greater amounts of antibody than their B220(+) counterparts. The pattern of cellular differentiation after transfer indicates that B220(-) memory B cells act as stable self-replenishing intermediates that arise from B220(+) memory B cells and produce antibody-secreting cells on rechallenge with antigen. Cell surface phenotype and Ig isotype expression divide the B220(-) compartment into two main subsets with distinct patterns of integrin and coreceptor expression. Thus, we identify new cellular components of B cell memory and propose a model for long-term protective immunity that is regulated by a complex balance of committed memory B cells with subspecialized immune function.
NADPH Oxidases in the Kidney (2006)

NADPH oxidases have a distinct cellular localization in the kidney. Reactive oxygen species (ROS) are produced in the kidney by fibroblasts, endothelial cells (EC), vascular smooth muscle cells (VSMC), mesangial cells (MCs), tubular cells, and podocyte cells. All components of the phagocytic NADPH oxidase, as well as the Nox-1 and -4, are expressed in the kidney, with a prominent expression in renal vessels, glomeruli, and podocytes, and cells of the thick ascending limb of the loop of Henle (TAL), macula densa, distal tubules, collecting ducts, and cortical interstitial fibroblasts. NADPH oxidase activity is upregulated by prolonged infusion of angiotensin II (Ang II) or a high salt diet. Since these are major factors underlying the development of hypertension, renal NADPH oxidase may have an important pathophysiological role. Indeed, recent studies with small interference RNAs (siRNAs) targeted to p22( phox ) implicate p22( phox ) in Ang II-induced activation of renal NADPH oxidase and the development of oxidative stress and hypertension, while studies with apocynin implicate activation of p47( phox ) in the development of nephropathy in a rat model of type 1 diabetes mellitus (DM). Experimental studies of the distribution, signaling, and function of NADPH oxidases in the kidney are described.
A single olfactory receptor specifically binds a set of odorant molecules (2002)

The sense of smell is mediated by the initiation of action potential in olfactory sensory neurons during odor stimulation. However, little is known about odorant-olfactory receptor (OR) recognition mechanisms. In the present work, we identified the structural motifs of odorant molecules required to activate mouse OR912-93 by detection of the odorant response using calcium measurement in cells transfected with OR and G(alpha)q and G(alpha)15 proteins. The use of sets of odorants led to the identification of ketones with an aliphatic carbon chain length >or= four carbon atoms and a carbonyl group preferentially located in position C2 or C3. The threshold of detection of these odorants is as low as 10(-6)-10(-8)m. No other odorant ligand, out of 70 representatives of the odorant world, was active. The human ortholog of OR912-93 is not functional, suggesting that apart from a stop-mutation located at the 5'-end that was corrected in the construct, it incurred other deleterious mutations during evolution.
Aggregopathy in Neurodegenerative Diseases: Mechanisms and Therapeutic Implication (2008)

Many neurodegenerative diseases such as Parkinson's, Alzheimer's, Huntington's and Lou Gehrig's disease are associated with the misfolding and aggregation of proteins. While the relevance of these aggregates for neuronal degeneration and their impact on cellular function is still a matter of debate, several experimental therapeutic approaches have been aimed at interfering with protein aggregation. In this review, we want to summarize the current understanding of aggregate formation and toxicity in neurodegenerative diseases with an emphasis on Parkinson's disease. Furthermore, we will discuss current treatment strategies in these diseases targeting aggregate formation and concurrent neuronal cell death in these diseases.
Identification of a Novel Proline-Arginine Motif Involved in CIN85-dependent Clustering of Cbl and Down-regulation of Epidermal Growth Factor Receptors (2003)

CIN85 is a multidomain adaptor protein implicated in Cbl-mediated down-regulation of receptor tyrosine kinases. CIN85 binding to Cbl is increased after growth factor stimulation and is critical for targeting receptor tyrosine kinases to clathrin-mediated endocytosis. Here we report the identification of a novel polyproline-arginine motif (PXXXPR), specifically recognized by the SH3 domains of CIN85 and its homologue CMS/CD2AP. This motif was indispensable for CIN85 binding to Cbl/Cbl-b, to other CIN85 SH3 domains' effectors, and for mediating an intramolecular interaction between the SH3-A domain and the proline-rich region of CIN85. Individual SH3 domains of CIN85 bound to PXXXPR peptides of Cbl/Cbl-b with micromolar affinities, whereas an extended structure of two or three SH3 domains bound with higher stoichiometry and increased affinity to the same peptides. This enabled full size CIN85 to simultaneously interact with multiple Cbl molecules, promoting their clustering in mammalian cells. The ability of CIN85 to cluster Cbl was important for ligand-induced stabilization of CIN85.Cbl.epidermal growth factor receptor complexes, as well as for epidermal growth factor receptor degradation in the lysosome. Thus, specific interactions of CIN85 SH3 domains with the PXXXPR motif in Cbl play multiple roles in down-regulation of receptor tyrosine kinases.
MUC2 mucin is a major carrier of the cancer-associated sialyl-Tn antigen in intestinal metaplasia and gastric carcinomas (2009)

Changes in mucin protein expression and in glycosylation are common features in pre-neoplastic lesions and cancer and are therefore used as cancer-associated markers. De novo expression of intestinal mucin MUC2 and cancer-associated sialyl-Tn antigen are frequently observed in intestinal metaplasia (IM) and gastric cancer. However, despite that these antigens often co-localize, MUC2 has not been demonstrated to be a carrier of sialyl-Tn. By using the in situ proximity ligation assay (in situ PLA), we herein could show that MUC2 is a major carrier of the sialyl-Tn antigen in all IM cases and in most gastric carcinoma cases. The requirement by in situ PLA for the presence of both antigens in close proximity increases the selectivity compared to measurement of co-localization, as determined by immunohistochemistry. Identification of the mucin which is the carrier of a carbohydrate structure offers unique advantages for future development of more accurate diagnostic and prognostic markers.
Impaired Antibacterial Host Defense in Mice Lacking the N-formylpeptide Receptor (1999)

N-formylpeptides derive from bacterial and mitochondrial proteins, and bind to specific receptors on mammalian phagocytes. Since binding induces chemotaxis and activation of phagocytes in vitro, it has been postulated that N-formylpeptide receptor signaling in vivo may be important in antimicrobial host defense, although direct proof has been lacking. Here we test this hypothesis in mice lacking the high affinity N-formylpeptide receptor (FPR), created by targeted gene disruption. FPR-/- mice developed normally, but had increased susceptibility to challenge with Listeria monocytogenes, as measured by increased mortality compared with wild-type littermates. FPR-/- mice also had increased bacterial load in spleen and liver 2 d after infection, which is before development of a specific cellular immune response, suggesting a defect in innate immunity. Consistent with this, neutrophil chemotaxis in vitro and neutrophil mobilization into peripheral blood in vivo in response to the prototype N-formylpeptide fMLF (formyl-methionyl-leucyl-phenylalanine) were both absent in FPR-/- mice. These results indicate that FPR functions in antibacterial host defense in vivo.
Binaural Source Localization and Spatial Audio Reproduction for Telepresence Applications (2007)

Telepresence is generally described as the feeling of being immersed in a remote environment, be it virtual or real. A multimodal telepresence environment, equipped with modalities such as vision, audition, and haptic, improves immersion and augments the overall perceptual presence. The present work focuses on acoustic telepresence at both the teleoperator and operator sites. On the teleoperator side, we build a novel binaural sound source localizer using generic Head Related Transfer Functions (HRTFs). This new localizer provides estimates for the direction of a single sound source given in terms of azimuth and elevation angles in free space by using only two microphones. It also uses an algorithm that is efficient compared to the currently known algorithms used in similar localization processes. On the operator side, the paper addresses the problem of spatially interpolating HRTFs for densely sampled high-fidelity 3D sound synthesis. In our telepresence application scenario the synthesized 3D sound is presented to the operator over headphones and shall achieve a high-fidelity acoustic immersion. Using measured HRTF data, we create interpolated HRTFs between the existing functions using a matrix-valued interpolation function. The comparison with existing interpolation methods reveals that our new method offers superior performance and is capable of achieving high-fidelity reconstructions of HRTFs.
Discovery and High-Throughput Screening of Heteroleptic Iridium Complexes for Photoinduced Hydrogen Production (2005)

The catalytic process of photoinduced hydrogen generation via the reduction of water has been investigated. The use of parallel synthetic techniques has facilitated the synthesis of a 32 member library of heteroleptic iridium complexes that was screened, using high-throughput photophysical techniques, to identify six potential photosensitizers for use in catalytic photoinduced hydrogen production. A Pd/Ni thin film hydrogen selective sensor allowed for rapid quantification of hydrogen produced via illumination of aqueous systems of the photosensitizer, tris(2,2'-dipyridyl)dichlorocobalt ([Co(bpy)(3)]Cl(2)), and triethanolamine (a sacrificial reductant) with ultra-bright light emitting diodes (LEDs). The use of an 8-well parallel photoreactor expedited the investigation of the hydrogen evolution process and facilitated mechanistic studies. All six compounds investigated produced considerably more hydrogen than commonly utilized photosensitizers and had relative quantum efficiencies of hydrogen production up to 37 times greater than that of Ru(bpy)(3)(2+).
High performance, low cost carbon nanotube yarn based 3D printed electrodes compatible with a conventional screen printed electrode system (2017)

3D printing technology has been widely used as a rapid prototyping fabrication tool in several fields, including electrochemistry. In this work, we incorporate 3D printing technology with carbon nanotube yarns for electrochemical sensing of dopamine in the presence of ascorbic acid and uric acid. The novel 3D printed electrode provides a circular concavity detection zone with grooves to insert three electrodes. The electrode connections are fully compatible with conventional screen printed electrode workstation setups. The CNT yarn 3D printed electrode showed excellent electrocatalytic activity for the redox reaction of dopamine (DA) in the presence of ascorbic acid (AA) and uric acid (UA). Three well-defined sharp and fully resolved anodic peaks were found with the peak potentials using cyclic voltammetry (CV) at 50 mV, 305 mV, and 545 mV for AA, DA, and UA respectively and using differential pulse voltammetry (DPV) at 91 mV, 389 mV, and 569 mV, respectively. DA detection limit was 0.87 ± 0.09 μM. The CNT yarn 3D printed electrode displayed high reproducibility and stability. The electrode design enables the study of electrode reactions at the sidewall of CNTs, which cannot be performed using electrodes made by conventional fabrication methods. The new fabrication method provides a new platform to prototype new electrode materials for electrochemistry, providing a low-cost, customizable design compatible existing screen printed electrodes technology.
GLIMPSE: a tool to search through entire file systems (1994)

GLIMPSE, which stands for GLobal IMPlicit SEarch, provides indexing and query schemes for file systems. The novelty of glimpse is that it uses a very small index — in most cases 2-4 % of the size of the text — and still allows very flexible full-text retrieval including Boolean queries, approximate matching (i.e., allowing misspel-ling), and even searching for regular expressions. In a sense, glimpse extends agrep to entire file systems, while preserving most of its functionality and simplicity. Query times are typically slower than with inverted indexes, but they are still fast enough for many applications. For example, it took 5 seconds of CPU time to find all 19 occurrences of Usenix AND Winter in a file system containing 69MB of text spanning 4300 files. Glimpse is particularly designed for personal information, such as one’s own file system. The main characteristic of per-sonal information is that it is non-uniform and includes many types of documents. An information retrieval sys-tem for personal information should support many types of queries, flexible interaction, low overhead, and cus-tomization, All these are important features of glimpse.
Measures of kidney function by minimally invasive techniques correlate with histological glomerular damage in SCID mice with adriamycin-induced nephropathy (2015)

Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner. To date, most studies of murine nephropathy depend on unreliable markers of renal physiological function, exemplified by measuring blood levels of creatinine and urea, and on various end points necessitating sacrifice of experimental animals to assess histological damage, thus counteracting the principles of Replacement, Refinement and Reduction. Here, we applied two novel minimally invasive techniques to measure kidney function in SCID mice with adriamycin-induced nephropathy. We employed i) a transcutaneous device that measures the half-life of intravenously administered FITC-sinistrin, a molecule cleared by glomerular filtration; and ii) multispectral optoacoustic tomography, a photoacoustic imaging device that directly visualises the clearance of the near infrared dye, IRDye 800CW carboxylate. Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury. These technologies provide clinically relevant functional data and should be widely adopted for testing the efficacies of novel therapies. Moreover, their use will also lead to a reduction in experimental animal numbers.
Synthesis and central nervous system actions of thyrotropin‐releasing hormone analogs containing a 1‐substituted 2‐oxoimadazolidine moiety* (1989)

A series of thyrotropin-releasing hormone (TRH) analogs in which the pyroglutamic acid residue was replaced by (S)-2-oxoimidazolidine-4-carboxylic acid (Oic-OH) and the related derivatives was prepared, and the central nervous system (CNS) actions were examined. Of these, 1-benzyl-Oic-His-Pro-NH2 (2c) showed the most potent activities, which were 1.5-8 times greater than those of TRH. Moreover, the thyrotropin (TSH)-releasing activity of 2c was about 1/16 times weaker than that of TRH.
Endoscopic and histologic evidence of persistent mucosal healing and correlation with clinical improvement following sustained infliximab treatment for Crohn's disease (2005)

Endoscopic and histologic evidence of mucosal healing was associated with a sustained reduction in the expression of inflammatory markers. Infliximab-induced improvement in the clinical signs and symptoms of Crohn's disease was associated with endoscopic and histologic evidence of sustained mucosal healing.
Phosphorylation of a novel zinc-finger-like protein, ZPR9, by murine protein serine/threonine kinase 38 (MPK38) (2002)

We have identified previously a new murine protein serine/threonine kinase, MPK38, closely related to the sucrose-non-fermenting protein kinase family [Gil, Yang, Lee, Choi and Ha (1997) Gene 195, 295–301]. Using the C-terminal half of the putative human counterpart of MPK38, HPK38, as a bait in a yeast two-hybrid screen of a human HeLa cDNA library, it was discovered that the zinc-finger-motif-containing protein, termed zinc-finger-like protein 9 (ZPR9), bound both HPK38 and MPK38. In a co-expression assay, ZPR9 associated with MPK38 in vivo, and we showed that the ZPR9 is also phosphorylated by MPK38. In addition, ZPR9 physically interacts with itself in mammalian cells. The ZPR9 cDNA hybridized with a mRNA species of approx. 1.7kb in Northern-blot analysis. The ZPR9 transcript was detected in all tissues examined, including lung, kidney, spleen, liver and brain. Co-expression of ZPR9 with MPK38 caused the accumulation of ZPR9 in the nucleus. These findings suggest a potentially important role for ZPR9 in MPK38-mediated signal transduction, and that ZPR9 is a physiological substrate of MPK38 in vivo.
Interleukin-1 induces human bone marrow-derived fibroblasts to produce multilineage hematopoietic growth factors. (1987)

Interleukin-1 (IL-1) has been shown to induce stromal cells, including endothelial cells and fibroblasts, to produce multilineage hematopoietic growth factors. Although both of these cell types are well-described elements of the hematopoietic microenvironment, previous studies of IL-1-inducible colony-stimulating factor responses have utilized fibroblasts and endothelial cells from nonhematopoietic sites. Since we hypothesize that this intercellular growth network is active in the hematopoietic microenvironment, we sought to determine the responsiveness of bone marrow fibroblasts to IL-1. We demonstrate here that recombinant human IL-1 alpha and beta stimulate the dose-dependent release of granulocyte-macrophage colony-stimulating activity (GM-CSA) and burst-promoting activity (BPA) by cultured human bone marrow fibroblasts. We conclude that bone marrow fibroblasts produce hematopoietic growth factors in response to interleukin-1, and that this may be a mechanism by which stromal cells regulate cellular growth and differentiation within the hematopoietic microenvironment.
Molecular Cloning and Overexpression of the Gene Encoding an NADPH-Dependent Carbonyl Reductase fromCandida magnoliae, Involved in Stereoselective Reduction of Ethyl 4-Chloro-3-oxobutanoate (2000)

An NADPH-dependent carbonyl reductase (S1) isolated from Candida magnoliae catalyzed the reduction of ethyl 4-chloro-3-oxobutanoate (COBE) to ethyl (S)-4-chloro-3-hydroxybutanoate (CHBE), with a 100% enantiomeric excess, which is a useful chiral building block for the synthesis of pharmaceuticals. The gene encoding the enzyme was cloned and sequenced. The S1 gene comprises 849 bp and encodes a polypeptide of 30,420 Da. The deduced amino acid sequence showed a high degree of similarity to those of the other members of the short-chain alcohol dehydrogenase superfamily. The S1 gene was overexpressed in Escherichia coli under the control of the lac promoter. The enzyme expressed in E. coli was purified to homogeneity and had the same catalytic properties as the enzyme from C. magnoliae did. An E. coli transformant reduced COBE to 125 g/l of (S)-CHBE, with an optical purity of 100% enantiomeric excess, in an organic solvent two-phase system.