gebhart/patrepeval huggingface dataset:
GPVI and α2β1 play independent critical roles during platelet adhesion and aggregate formation to collagen under flow (2005)

The roles of the 2 major platelet-collagen receptors, glycoprotein VI (GPVI) and integrin alpha2beta1, have been intensely investigated using a variety of methods over the past decade. In the present study, we have used pharmacologic and genetic approaches to study human and mouse platelet adhesion to collagen under flow conditions. Our studies demonstrate that both GPVI and integrin alpha2beta1 play significant roles for platelet adhesion to collagen under flow and that the loss of both receptors completely ablates this response. Intracellular signaling mediated by the cytoplasmic adaptor Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) but not by the transmembrane adaptor linker for activation of T cells (LAT) is critical for platelet adhesion to collagen under flow. In addition, reduced GPVI receptor density results in severe defects in platelet adhesion to collagen under flow. Defective adhesion to collagen under flow is associated with prolonged tail-bleeding times in mice lacking one or both collagen receptors. These studies establish platelet-collagen responses under physiologic flow as the consequence of a close partnership between 2 structurally distinct receptors and suggest that both receptors play significant hemostatic roles in vivo.
LY503430: Pharmacology, Pharmacokinetics, and Effects in Rodent Models of Parkinson's Disease (2006)

Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-subtype of glutamate receptors have led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present studies we characterized a novel AMPA receptor potentiator, LY503430, on recombinant human GLU(A1-4) and native preparations in vitro, and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that at submicromolar concentrations LY503430 selectively enhanced glutamate-induced calcium influx into HEK293 cells transfected with human GLU(A1), GLU(A2), GLU(A3), or GLU(A4) AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal and substantia nigra neurones. LY503430 had good oral bioavailability in both rats and dogs. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity following unilateral infusion of 6-hyrdoxydopamine (6-OHDA) into either the substantia nigra or the striatum of rats and that following systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after (6 or 14 days) the lesion was established. LY503430 also produced some increase in brain derived neurotrophic factor (BDNF) in the substantia nigra and a dose-dependent increase in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators such as LY503430 offer the potential of a new disease modifying therapy for Parkinson's disease.
Synthesis of Fluorescence‐Labelled Glycosidic Prodrugs Based on the Cytotoxic Antibiotic Duocarmycin (2010)

Abstract The synthesis of the glycosidic prodrugs (1 S )‐ 30a , (1 S ,10 R )‐ 30b and (1 S ,10 R )‐ 32 labelled with different fluorescence dyes at different positions at the aromatic A‐ring in 2 is described; the compounds are structurally based on the cytotoxic antibiotic duocarmycin SA. For binding, the amino compounds (1 S )‐ 3a and (1 S ,10 R )‐ 3b were treated with the commercially available succinimides of the dyes 5‐SFX ( 29 ) and D10162 ( 31 ), respectively.
Suggested guidelines for the diagnosis and management of urea cycle disorders (2012)

Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.
The Elasticity of a Single Supercoiled DNA Molecule (1996)

Single linear DNA molecules were bound at multiple sites at one extremity to a treated glass cover slip and at the other to a magnetic bead. The DNA was therefore torsionally constrained. A magnetic field was used to rotate the beads and thus to coil and pull the DNA. The stretching force was determined by analysis of the Brownian fluctuations of the bead. Here the elastic behavior of individual lambda DNA molecules over- and underwound by up to 500 turns was studied. A sharp transition was discovered from a low to a high extension state at a force of approximately 0.45 piconewtons for underwound molecules and at a force of approximately 3 piconewtons for overwound ones. These transitions, probably reflecting the formation of alternative structures in stretched coiled DNA molecules, might be relevant for DNA transcription and replication.
The laminin-binding activity of the alpha 7 integrin receptor is defined by developmentally regulated splicing in the extracellular domain. (1997)

The expression pattern of the laminin-binding alpha 7 beta 1 integrin is developmentally regulated in skeletal, cardiac, and smooth muscle. The X1/X2 alternative splicing in the extracellular domain of alpha 7 is found in the variable region between conserved alpha-chain homology repeat domains III and IV, a site implicated in ligand binding. To assess differences in X1/X2 isoform activity, we generated MCF-7 cell lines transfected with alpha 7-X1/X2 cDNAs. Transfectants expressing the alpha 7-X2 variant adhered rapidly to laminin 1, whereas those expressing alpha 7-X1 failed to attach. That alpha 7-X1 exists in an inactive state was established in assays using an activating beta 1 antibody that induced X1-dependent cell adhesion and spreading. Furthermore, the activation of alpha 7-X1 was cell type specific, and when expressed in HT1080 cells, the integrin was converted into a fully functional receptor capable of promoting adhesion. Thus, the expression of the alpha 7-X1/X2 integrin is a novel mechanism that regulates receptor affinity states in a cell-specific context and may modulate integrin-dependent events during muscle development and repair.
Exploring 3D Interaction in Alternate Control-Display Space Mappings (2007)

The desire to have intuitive, seamless 3D interaction fuels research exploration into new approaches to 3D interaction. However, within these explorations we continue to rely on Brunelleschi's perspective for display and map the interactive control space directly into it without much thought on the effect that this default mapping has. In contrast, there are many possibilities for creating 3D interaction spaces, thus making it important to run user studies to examine these possibilities. Options in mapping the control space to the display space for 3D interaction have previously focused on the manipulation of control-display ratio or gain. In this paper, we present a conceptual framework that provides a more general control-display description that includes mappings for flip, rotation, skew, as well as scale (gain). We conduct a user study to explore 3D selection and manipulation tasks in three of these different mappings in comparison to the commonly used mapping (perspective mapping of control space to a perspective display). Our results show interesting differences between interactions and user preferences in these mappings and indicate that all may be considered viable alternatives. Together this framework and study open the door to further exploration of 3D interaction variations
Visualizing Changes of Hierarchical Data using Treemaps (2007)

While the treemap is a popular method for visualizing hierarchical data, it is often difficult for users to track layout and attribute changes when the data evolve over time. When viewing the treemaps side by side or back and forth, there exist several problems that can prevent viewers from performing effective comparisons. Those problems include abrupt layout changes, a lack of prominent visual patterns to represent layouts, and a lack of direct contrast to highlight differences. In this paper, we present strategies to visualize changes of hierarchical data using treemaps. A new treemap layout algorithm is presented to reduce abrupt layout changes and produce consistent visual patterns. Techniques are proposed to effectively visualize the difference and contrast between two treemap snapshots in terms of the map items' colors, sizes, and positions. Experimental data show that our algorithm can achieve a good balance in maintaining a treemap's stability, continuity, readability, and average aspect ratio. A software tool is created to compare treemaps and generate the visualizations. User studies show that the users can better understand the changes in the hierarchy and layout, and more quickly notice the color and size differences using our method.
Longitudinal mode behavior and tunability of separately pumped (GaAl)As lasers (1984)

A three-segment laser, when separately pumped, shows both frequency switching and continuous tuning with a modulation current applied to the middle segment. The wavelength changes are attributed to gain peak shift with the carrier concentration and carrier-induced index change. A total wavelength change of 61 Å, a continuous tuning range of 4.1 Å, and a tuning rate of −0.74 Å/mA are obtained. The laser may be useful in optical FM fiber communication.
Privacy-preserving data integration and sharing (2004)

Integrating data from multiple sources has been a longstanding challenge in the database community. Techniques such as privacy-preserving data mining promises privacy, but assume data has integration has been accomplished. Data integration methods are seriously hampered by inability to share the data to be integrated. This paper lays out a privacy framework for data integration. Challenges for data integration in the context of this framework are discussed, in the context of existing accomplishments in data integration. Many of these challenges are opportunities for the data mining community.
Magnetic Field Effects in Biology: A Survey of Possible Mechanisms with Emphasis on Radical-Pair Recombination (1995)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMagnetic Field Effects in Biology: A Survey of Possible Mechanisms with Emphasis on Radical-Pair RecombinationCharles B. GrissomCite this: Chem. Rev. 1995, 95, 1, 3–24Publication Date (Print):January 1, 1995Publication History Published online1 May 2002Published inissue 1 January 1995https://pubs.acs.org/doi/10.1021/cr00033a001https://doi.org/10.1021/cr00033a001research-articleACS PublicationsRequest reuse permissionsArticle Views2184Altmetric-Citations338LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Results from a phase II randomized, placebo-controlled, double-blind trial suggest improved PFS with the addition of pertuzumab to gemcitabine in patients with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer (2007)

5507 Background: Pertuzumab (P) is a humanized monoclonal antibody that blocks the ability of HER2 to heterodimerize with other HER/ErbB receptors. As a single agent, P has demonstrated clinical activity in relapsed/refractory epithelial ovarian cancer (EOC). Since platinum-resistant (CDDP-R) EOC remains a difficult disease to treat, this phase II study was conducted to determine if addition of P to gemcitabine (G) would improve results. Methods: Patients with CDDP-R EOC (including ovarian, fallopian tube, or primary peritoneal cancer) who had received up to one prior treatment for CDDP-R disease were randomized to Gem 800 mg/m 2 on D1, 8 of a 21-day cycle ± P or placebo (pl). P was given as an 840 mg initial dose followed by 420mg IV every 3 weeks. Tumor response was assessed by RECIST every 6 weeks using GOG criteria. The primary endpoint was progression free survival (PFS). Results: One hundred thirty patients (n = 65 each treatment cohort) were treated. Clinical characteristics were balanced between the treatment groups. Pts received a median of 2 prior regimens (range 1–6) for EOC. Based on 83 events, the adjusted hazard ratio for PFS was 0.67 (95% CI: 0.43–1.02), p =0.06 in favor of P+Gem. The median PFS was 3.0 months (0–8.7 months) vs. 2.6 months (0–9+ months), and the PFS rate at 4 months was 49% vs. 34% in the P+Gem and Gem/pl arms, respectively. The most common AEs increased in the P-treated pts were fatigue, nausea, diarrhea, back pain, Gr 3–4 neutropenia, rash, headache, stomatitis, epistaxis, and rhinorrhea. Clinically significant CHF was reported in one patient in the pertuzumab cohort. There was no imbalance in the LVEF results between treatment arms. One patient who received pertuzumab + gemcitabine experienced an adverse event that resulted in death (hemolytic-uremic syndrome). Conclusions: These data suggest that pertuzumab may add activity to gemcitabine as reflected by improvements in PFS in patients with CDDP-R ovarian, primary peritoneal, or fallopian tube cancer. Survival data will be presented at ASCO. No significant financial relationships to disclose.
ChemInform Abstract: REACTIONS OF HALOKETENES WITH ALLYL ETHERS AND THIOETHERS: A NEW TYPE OF CLAISEN REARRANGEMENT (1983)

Abstract Aus den AIIyl‐Verbindungen (I) erhält man mit Dichlorketen (II) die Einschiebungsprodukte (III) neben den Cycloaddukten (IV).
Small Interfering RNA-Induced Transcriptional Gene Silencing in Human Cells (2004)

Small interfering RNA (siRNA) and microRNA silence genes at the transcriptional, posttranscriptional, and/or translational level. Using human tissue culture cells, we show that promoter-directed siRNA inhibits transcription of an integrated, proviral, elongation factor 1alpha (EF1A) promoter-green fluorescent protein reporter gene and of endogenous EF1A. Silencing was associated with DNA methylation of the targeted sequence, and it required either active transport of siRNA into the nucleus or permeabilization of the nuclear envelope by lentiviral transduction. These results demonstrate that siRNA-directed transcriptional silencing is conserved in mammals, providing a means to inhibit mammalian gene function.
Research Problems for Scalable Internet Resource Discovery (1993)

Abstract : Over the past several years, a number of information discovery and access tools have been introduced to the Internet, including Archie, Gopher, Netfind, and WAIS. These tools have become quite popular and are helping to redefine how people think about wide area network applications. Yet they are not well suited to supporting the future information infrastructure, which will be characterized by enormous data volume, rapid growth in the user base, and burgeoning data diversity. In this paper, we indicate trends in these three dimensions, and survey problems these trends will create for current approaches. We then suggest several promising directions of future resource discovery research, along with some initial results from projects carried out by members of the Internet Research Task Force Research Group on Resource Discovery and Directory Service.
Novel Inhibitors of Erm Methyltransferases from NMR and Parallel Synthesis (1999)

The Erm family of methyltransferases confers resistance to the macrolide-lincosamide-streptogramin type B (MLS) antibiotics through the methylation of 23S ribosomal RNA. Upon the methylation of RNA, the MLS antibiotics lose their ability to bind to the ribosome and exhibit their antibiotic activity. Using an NMR-based screen, we identified a series of triazine-containing compounds that bind weakly to ErmAM. These initial lead compounds were optimized by the parallel synthesis of a large number of analogues, resulting in compounds which inhibit the Erm-mediated methylation of rRNA in the low micromolar range. NMR and X-ray structures of enzyme/inhibitor complexes reveal that the inhibitors bind to the S-adenosylmethionine binding site on the Erm protein. These compounds represent novel methyltransferase inhibitors that serve as new leads for the reversal of Erm-mediated MLS antibiotic resistance.
Posttranslational N-glycosylation takes place during the normal processing of human coagulation factor VII (2004)

N-glycosylation is normally a cotranslational process that occurs during translocation of the nascent protein to the endoplasmic reticulum. In the present study, however, we demonstrate posttranslational N-glycosylation of recombinant human coagulation factor VII (FVII) in CHO-K1 and 293A cells. Human FVII has two N-glycosylation sites (N145 and N322). Pulse-chase labeled intracellular FVII migrated as two bands corresponding to FVII with one and two N-glycans, respectively. N-glycosidase treatment converted both of these band into a single band, which comigrated with mutated FVII without N-glycans. Immediately after pulse, most labeled intracellular FVII had one N-glycan, but during a 1-h chase, the vast majority was processed into FVII with two N-glycans, demonstrating posttranslational N-glycosylation of FVII. Pulse-chase analysis of N-glycosylation site knockout mutants demonstrated cotranslational glycosylation of N145 but primarily or exclusively posttranslational glycosylation of N322. The posttranslational N-glycosylation appeared to take place in the same time frame as the folding of nascent FVII into a secretion-competent conformation, indicating a link between the two processes. We propose that the cotranslational conformation(s) of FVII are unfavorable for glycosylation at N332, whereas a more favorable conformation is obtained during the posttranslational folding. This is the first documentation of posttranslational N-glycosylation of a non-modified protein in mammalian cells with an intact N-glycosylation machinery. Thus, the present study demonstrates that posttranslational N-glycosylation can be a part of the normal processing of glycoproteins.
Sirt1-Independent Mechanisms of the Putative Sirtuin Enzyme Activators SRT1720 and SRT2183 (2010)

Structural features of these molecules may account for false-positive activation using fluorescence-based assays.
Introduction of unnatural amino acids into chalcone isomerase (1991)

The active site cysteine residue of chalcone isomerase was rapidly and selectively modified under denaturing conditions with a variety of electrophilic reagents. These denatured and modified enzyme were renatured to produce enzyme derivatives containing a series of unnatural amino acids in the active site. Addition of methyl, ethyl, butyl, heptyl, and benzyl groups to the cysteine sulfur does not abolish catalytic activity, although the activity decreases as the steric bulk of the amino acid side-chain increases. Modification of the cysteine to introduce a charged homoglutamate or a neutral homoglutamine analogue results in retention of 22% of the catalytic activity. Addition of a methylthio group (SMe) to the cysteine residue of native chalcone isomerase preserves 85% of the catalytic activity measured with 2',4',4-trihydroxychalcone, 2',4',6',4-tetrahydroxychalcone, or 2'-hydroxy-4-methoxychalcone as substrates. The competitive inhibition constant for 4',4-dihydroxychalcone, the substrate inhibition constant for 2',4',4-trihydroxychalcone, and other steady-state kinetic parameters for the methanethiolated enzyme are very similar to those of the native enzyme. The strong binding of 4',4-dihydroxychalcone to the methanethiolated enzyme shows that there is no steric repulsion between this modified amino acid residue and the substrate analogue. This structure-activity study clearly demonstrates that the active site cysteine residue does not function as an acid-base or nucleophilic group in producing the catalysis or substrate inhibition observed with chalcone isomerase. The method presented in this paper allows for the rapid introduction of a series of unnatural amino acids into the active site as a means of probing the structure-function relationship.