gebhart/patrepeval huggingface dataset:
Glucagon Antagonists: Contribution to Binding and Activity of the Amino-terminal Sequence 1–5, Position 12, and the Putative α-Helical Segment 19–27 (1989)

Glucagon binding to and recognition by its cell surface receptor is the necessary first step in the cascade of events leading to the activation of adenylate cyclase by the hormone. It has long been presumed that glucagon adopts an ordered conformation upon binding to its membrane-bound receptor. A recent model of this three-dimensional structure based on biophysical data, predicts beta-turns at positions 2-5, 10-13, and 15-18, and an alpha-helical region between residues 19-27. Our approach in the design of antagonists of glucagon was to elucidate the steric and electronic features that stabilize these secondary structures to obtain analogs that bind with high affinity to the receptor but do not activate adenylate cyclase. Nineteen glucagon analogs incorporating structural changes at the amino-terminal sequence 1-5, at positions 9 and 12, and at the carboxyl-terminal helical region were synthesized. Des-His1-[Glu9]glucagon amide was recently shown to be a competitive inhibitor. Our synthetic studies in combination with this modification have resulted in seven new glucagon antagonists. The implications for the structural and conformational properties required for binding and activity of glucagon and the glucagon peptide family are discussed.
Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 13 µm (2005)

We demonstrate a high-speed multi-functional spectral-domain optical coherence tomography system, using a broadband light source centered at 1.3 microm and two InGaAs line scan cameras capable of acquiring individual axial scans in 24.4 micros, at a rate of 18,500 axial scans per second. Fundamental limitations on the accuracy of phase determination as functions of signal-to-noise ratio and lateral scan speed are presented and their relative contributions are compared. The consequences of phase accuracy are discussed for both Doppler and polarization-sensitive OCT measurements. A birefringence artifact and a calibration procedure to remove this artifact are explained. Images of a chicken breast tissue sample acquired with the system were compared to those taken with a time-domain OCT system for birefringence measurement verification. The ability of the system to image pulsatile flow in the dermis and to perform functional imaging of large volumes demonstrates the clinical potential of multifunctional spectral-domain OCT.
Heparin-Associated Thrombocytopenia: A Prospective Comparison of Bovine Lung Heparin, Manufactured by a New Process, and Porcine Intestinal Heparin (1986)

Heparin-associated thrombocytopenia has been reported most commonly with bovine lung preparations. We prospectively evaluated the incidence of thrombocytopenia in 43 patients receiving intravenous continuous infusions of either bovine lung heparin, manufactured by a new process, or a standard porcine intestinal mucosa heparin for a minimum of five days in a double-blind, randomized fashion. The decision to continue heparin therapy beyond five days was made by the patient's primary physician. All patients had documented acute thromboembolic disease, pretherapy platelet counts greater than 150 000/mm3, and no evidence of prior coagulation disturbance. No patients had undergone cardiopulmonary bypass or hemodialysis within seven days previous to the initiation of heparin therapy. Thrombocytopenia was defined as a decline in platelet count from the normal range of 150 000-350 000/mm3 to less than 100 000/mm3. Thrombocytopenia occurred in one patient (4.6 percent) receiving bovine lung heparin on day nine of therapy and in no patients (0 percent) receiving porcine intestinal mucosa heparin. Adverse reactions occurred in nine patients (42.9 percent) receiving porcine intestinal heparin and five patients (22.7 percent) receiving bovine lung heparin. This difference was not statistically significant. The results of this study indicate that the incidence of thrombocytopenia is low (less than five percent) with both bovine lung heparin, manufactured by a new process, and porcine intestinal mucosa heparin when therapy is limited to short therapeutic courses (less than 1 week).
Homozygous p.Ser267Phe in SLC10A1 is associated with a new type of hypercholanemia and implications for personalized medicine (2017)

SLC10A1 codes for the sodium-taurocholate cotransporting polypeptide (NTCP), which is a hepatocellular transporter for bile acids (BAs) and the receptor for hepatitis B and D viruses. NTCP is also a target of multiple drugs. We aimed to evaluate the medical consequences of the loss of function mutation p.Ser267Phe in SLC10A1. We identified eight individuals with homozygous p.Ser267Phe mutation in SLC10A1 and followed up for 8-90 months. We compared their total serum BAs and 6 species of BAs with 170 wild-type and 107 heterozygous healthy individuals. We performed in-depth medical examinations and exome sequencing in the homozygous individuals. All homozygous individuals had persistent hypercholanemia (P = 5.8 × 10<sup>-29</sup>). Exome sequencing excluded the involvement of other BA metabolism-associated genes in the hypercholanemia. Although asymptomatic, all individuals had low vitamin D levels. Of six adults that were subjected to bone mineral density analysis, three presented with osteoporosis/osteopenia. Sex hormones and blood lipids were deviated in all subjects. Homozygosity of p.Ser267Phe in SLC10A1 is associated with asymptomatic hypercholanemia. Individuals with homozygous p.Ser267Phe in SLC10A1 are prone to vitamin D deficiency, deviated sex hormones and blood lipids. Surveillance of these parameters may also be needed in patients treated with drugs targeting NTCP.
Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. (1997)

Vascular endothelial growth factor (VEGF) has been implicated in retinal neovascularization (NV), but it has been difficult to produce retinal NV with exogenous VEGF. We investigated the effect of increased VEGF expression in the retina using tissue-specific, gain-of-function transgenic mice in which the bovine rhodopsin promoter is coupled to the gene for human VEGF. Three founder mice were obtained and used to generate transgenic lines. One of the lines shows increased expression of VEGF in the retina by reverse transcription coupled to polymerase chain reaction and Northern blots, and the VEGF is localized to photoreceptors by immunohistochemistry. These mice demonstrate new vessels originating from the deep capillary bed of the retina that extend beneath the photoreceptor layer into the subretinal space where they form clumps of blood vessels surrounded by proliferated retinal pigmented epithelial cells. The appearance is similar to subretinal NV seen in some patients, except that the blood vessels originate from the retinal vasculature rather than the choroidal vasculature. One of the other two lines of mice did not show increased expression of VEGF and did not have NV; the other line showed retinal degeneration. This study demonstrates that over-expression of VEGF in the retina is sufficient to cause intraretinal and subretinal NV and provides a valuable new animal model.
ENHANCED IMMUNOGENICITY OF A GM2 GANGLIOSIDE VACCINE CONJUGATED TO KLH (1993)

Journal of Immunotherapy with Emphasis on Tumor Immunology: November 1993 - Volume 14 - Issue 4 - p 363
Technique for Quantitative Detection of Specific DNA Sequences Using Alternately Binding Quenching Probe Competitive Assay Combined with Loop-Mediated Isothermal Amplification (2007)

We describe a novel technique for a simple, rapid, and reliable quantitative detection of specific DNA sequences using an alternately binding quenching probe (AB-QProbe) that binds to either the gene of interest (target) or an internal standard (competitor) in combination with loop-mediated isothermal amplification (LAMP). The AB-QProbe is a singly labeled oligonucleotide bearing a fluorescent dye at the 5' end. The fluorescence intensity of the AB-QProbe reflects the ratio of the LAMP products from the target and competitor. We amplified the target and competitor by LAMP under isothermal conditions with high specificity, efficiency, and rapidity and calculated the starting quantity of the target from the fluorescence intensities at the beginning and end of LAMP. We call this technique alternately binding quenching probe competitive LAMP (ABC-LAMP). We quantified amoA, which encodes the ammonia-oxidizing enzyme in environmental bacteria, as a model target by ABC-LAMP, real-time PCR, and real-time turbidimetry of LAMP. By comparison, the accuracy of ABC-LAMP was found to be similar to that of real-time PCR. Moreover, ABC-LAMP enables the accurate quantification of DNA in the presence of DNA amplification inhibitors such as humic acid, urea, and Triton X-100 that compromise the values measured by real-time PCR and real-time turbidimetry of LAMP.
Mechanism for Bupivacaine Depression of Cardiac Conduction (1985)

The effects of bupivacaine and lidocaine on cardiac conduction were compared in guinea pig ventricular muscle. Membrane potential was controlled using a single sucrose gap voltage clamp technique, and the maximum upstroke velocity of the action potential (Vmax) was used as an indicator of peak sodium current. Bupivacaine blocked cardiac sodium channels in a time- and voltage-dependent fashion. Although bupivacaine has a low affinity for rested and activated sodium channels, it avidly blocks inactivated channels (Kd = 9 X 10(-7) M). Bupivacaine-associated channels do not conduct and have their voltage dependence of inactivation shifted by about 33 mV to more negative potentials. At bupivacaine concentrations above 0.2 micrograms/ml, a substantial fraction of the channels become blocked during the cardiac action potential, while recovery from block during diastole proceeds relatively slowly with a time constant (tau) of 1,557 +/- 304 ms (n = 8). Thus, bupivacaine blocks sodium channels in a fast-in-slow-out fashion, and substantial block accumulates at 60-150 beats/min. In comparison, 5-10 micrograms/ml lidocaine also blocks a substantial fraction of channels during the action potential, but diastolic recovery from block is more rapid (tau = 153.8 +/- 51.2 ms, n = 4). Thus, lidocaine blocks channels in a fast-in-fast-out fashion. Consequently, even at toxic doses of lidocaine (i.e., 10 micrograms/ml), little accumulation of block occurs at normal heart rates. Sodium channel block by bupivacaine can be minimized by reducing heart rate, hyperpolarization, and shortening of action potential duration. However, alteration of these variables over clinically applicable ranges does not produce marked changes in bupivacaine effect. Our results provide a possible explanation for the clinical observation that when bupivacaine accidently gains access to the general circulation, cardiac conduction can be depressed seriously and such depression may be difficult to reverse.
Fitting models to biological data using linear and nonlinear regression : a practical guide to curve fitting (2004)

FITTING DATA WITH NONLINEAR REGRESSION FITTING DATA WITH LINEAR REGRESSION MODELS HOW NONLINEAR REGRESSION WORKS CONFIDENCE INTERVALS OF THE PARAMETERS COMPARING MODELS HOW DOES A TREATMENT CHANGE THE CURVE? FITTING RADIOLIGAND AND ENZYME KINETICS DATA FITTING DOES-RESPONSE CURVES FITTING CURVES WITH GRAPHPAD PRISM
Geo-centric language models for local business voice search (2009)

Voice search is increasingly popular, especially for local business directory assistance. However, speech recognition accuracy on business listing names is still low, leading to user frustration. In this paper, we present a new algorithm for geo-centric language model generation for local business voice search for mobile users. Our algorithm has several advantages: it provides a language model for any user in any location; the geographic area covered by the language model is adapted to the local business density, giving high recognition accuracy; and the language models can be pre-compiled, giving fast recognition time. In an experiment using spoken business listing name queries from a business directory assistance service, we achieve a 16.8% absolute improvement in recognition accuracy and a 3-fold speedup in recognition time with geocentric language models when compared with a nationwide language model.
Selectivity of BAFF/BLyS and APRIL for Binding to the TNF Family Receptors BAFFR/BR3 and BCMA (2005)

BAFF (B cell activating factor of the TNF family, also known as BlyS and TALL-1), a TNF family cytokine critical for the development and function of B cells, has been reported to bind to three receptors, BCMA (B cell maturation protein), TACI (transmembrane activator and CAML [calcium-modulator and cyclophilin ligand] interactor), and BAFFR (BAFF receptor), but with widely conflicting values for the affinity and selectivity of binding. BCMA and TACI additionally bind APRIL (a proliferation-inducing ligand), the TNF family ligand most homologous to BAFF. Using soluble, monomeric forms of the receptors, we demonstrate that BAFFR binds BAFF with K(D) approximately 16 nM, while BCMA binds with K(D) approximately 1.6 microM, indicating a approximately 100-fold selectivity for binding to BAFFR over BCMA. APRIL shows the opposite selectivity, binding to BCMA with K(D) approximately 16 nM while showing no detectable affinity for BAFFR (K(D) > 3 microM). The binding of BAFF or APRIL to these receptors is highly sensitive to assay-dependent avidity effects, likely explaining the widely ranging affinity values reported in the literature. Binding of BAFF to BCMA-Fc, a bivalent fusion protein consisting of the extracellular domain of BCMA fused to the hinge and CH1 and CH2 domains of human IgG1, in solution or coated onto an ELISA plate gave apparent binding affinities of approximately 0.63 and approximately 0.15 nM, respectively, compared to values of K(D(app)) <or= 30 and approximately 100 pM for the corresponding BAFFR/IgG1 fusion protein, BAFFR-Fc. The high selectivity of BAFF for BAFFR versus BCMA is thus partly obscured in these multivalent assays. The intrinsically high selectivity inferred from the measurements with monomeric receptor correlates well with in vivo data from knockout mice, providing a possible explanation for the observations that interruption of the BAFFR gene in the A/WySnJ mouse produces a phenotype similar to the BAFF knockout mouse, while the BCMA knockout mouse has no discernible B cell phenotype.
Vascular Endothelium as the Vulnerable Element in Tumours (1984)

The difference between blood vessels in tumours and normal tissues has been recognised for a long time, but little has been done to exploit this in cancer therapy. An overview is presented of the possible contribution of vascular mediated injury with several existing forms of treatment. Interventive radiology and, to some extent, hyperthermia are most obviously mediated through ischaemic cell death. The successful cure of many tumours with radiation, and the complete regressions seen with systemic chemotherapy may also be partially due to a vascular component of damage. The proliferation characteristics of endothelial cells in normal and tumour blood vessels are summarised. These have been derived from single injections or repeated administration of tritiated thymidine. A very large and consistent difference exists between the turnover times. The tumour endothelium is proliferating 20 to 2 000 times faster than any normal tissue endothelium in the adult. The single exception is the placenta which has even more rapid proliferation than the tumour endothelium. The large difference in proliferation rates, coupled with the poor wall structure, lack of innervation and lack of collateral supply, make the blood vessels an attractive target for tumour therapy. Possible means of utilizing this are outlined.
Annotate! a tool for collaborative information retrieval (2002)

Difficulties with Web based full text information retrieval (IR) systems include spurious matches, manually intensive document sifting, and the absence of communication or coordination between users. To address these difficulties, we introduce the Annotate! system which enables document annotations, and captures global usage history. Annotate! provides improved data and metadata clues to guide the user in a search session. Two data sets, declared in XML, are at the core of Annotate!: discussion data, a composite of documents and user annotations and session data which captures user timings at the various interface layers. We discuss a prototype implementation, and show that the collaborative infrastructure enabled by Annotate! can be predicted to improve the diffusion of ideas in the search community.
Effect of 2′-5′ Phosphodiesters on DNA Transesterification by Vaccinia Topoisomerase (2001)

Vaccinia topoisomerase forms a covalent DNA-(3'-phosphotyrosyl)-enzyme intermediate at a pentapyrimidine target site 5'-CCCTTp downward arrow in duplex DNA. By introducing single 2'-5' phosphodiesters in lieu of a standard 3'-5' phosphodiester linkage, we illuminate the contributions of phosphodiester connectivity to DNA transesterification. We find that the DNA cleavage reaction was slowed by more than six orders of magnitude when a 2'-5' linkage was present at the scissile phosphodiester (CCCTT(2')p downward arrow(5')A). Thus, vaccinia topoisomerase is unable to form a DNA-(2'-phosphotyrosyl)-enzyme intermediate. We hypothesize that the altered geometry of the 2'-5' phosphodiester limits the ability of the tyrosine nucleophile to attain a requisite, presumably apical orientation with respect to the 5'-OH leaving group. A 2'-5' phosphodiester located to the 3' side of the cleavage site (CCCTTp downward arrowN(2')p(5')N) reduced the rate of transesterification by a factor of 500. In contrast, 2'-5' phosphodiesters at four other sites in the scissile strand (TpCGCCCTpT downward arrowATpTpC) and five positions in the nonscissile strand (3'-GGGpApApTpApA) had no effect on transesterification rate. The DNAs containing 2'-5' phosphodiesters were protected from digestion by exonuclease III. We found that exonuclease III was consistently arrested at positions 1 and 2 nucleotides prior to the encounter of its active site with the modified 2'-5' phosphodiester and that the 2'-5' linkage itself was poorly hydrolyzed by exonuclease III.
Tumour-derived exosomes or microvesicles: another mechanism of tumour escape from the host immune system? (2005)

Tumour-derived exosomes or microvesicles: another mechanism of tumour escape from the host immune system?
Activated Epidermal Growth Factor Receptor–Stat-3 Signaling Promotes Tumor SurvivalIn vivoin Non–Small Cell Lung Cancer (2005)

Early-stage NSCLC tumors have activated EGFR-Stat3 signaling with low apoptosis. Our findings suggest that pStat3 expression may be helpful in identifying patients appropriate for treatment with EGFR tyrosine kinase inhibitors.
Identifying and Exploiting Spatial Regularity in Data Memory References (2003)

The growing processor/memory performance gap causes the performance of many codes to be limited by memory accesses. If known to exist in an application, strided memory accesses forming streams can be targeted by optimizations such as prefetching, relocation, remapping, and vector loads. Undetected, they can be a significant source of memory stalls in loops. Existing stream-detection mechanisms either require special hardware, which may not gather statistics for subsequent analysis, or are limited to compile-time detection of array accesses in loops. Formally, little treatment has been accorded to the subject; the concept of locality fails to capture the existence of streams in a program's memory accesses. The contributions of this paper are as follows. First, we define spatial regularity as a means to discuss the presence and effects of streams. Second, we develop measures to quantify spatial regularity, and we design and implement an on-line, parallel algorithm to detect streams - and hence regularity - in running applications. Third, we use examples from real codes and common benchmarks to illustrate how derived stream statistics can be used to guide the application of profile-driven optimizations. Overall, we demonstrate the benefits of our novel regularity metric as an instrument to detect potential for code optimizations affecting memory performance.
Effects of inorganic and organic promoters and inhibitors of calcium influx on stretch-induced myogenic tone of vascular tissues. (1989)

The static or dynamic stretch of helical strips or sudden increase of the transmural pressure produced contraction in cerebral and coronary arteries isolated from dogs and rabbits. The simultaneous recording of Ca transients and contractile activity showed that fluorescence intensity of fura-2 loaded cerebral artery increased during stretch activation. The contractile activation due to stretch was augmented by potentiators of Ca2+ influx, while it was attenuated by inhibitors of Ca2+ influx. The results suggest that contractile activation by mechanical stretch seems to provide a useful alternative technique to electrical and pharmacological stimuli for use in studies on contraction of vascular tissues and the effects of drugs and ions such as Ca antagonists and divalent cations which affect Ca2+ movement.
A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies (2002)

The gene encoding nuclear lamins A and C is mutated in at least three inherited disorders. Two of these, Emery-Dreifuss muscular dystrophy (EDMD-AD) and a form of dilated cardiomyopathy (CMD1A), involve muscle defects, and the other, familial partial lipodystrophy (FPLD), involves loss of subcutaneous adipose tissue. Mutations causing FPLD, in contrast to those causing muscle disorders, are tightly clustered within the C-terminal domain of lamin A/C. We investigated the expression and subcellular localization of FPLD lamin A mutants and found no abnormalities. We therefore set out to identify proteins interacting with the C-terminal domain of lamin A by screening a mouse 3T3-L1 adipocyte library in a yeast two-hybrid interaction screen. Using this approach, the adipocyte differentiation factor, sterol response element binding protein 1 (SREBP1) was identified as a novel lamin A interactor. In vitro glutathione S-transferase pull-down and in vivo co-immunoprecipitation studies confirmed an interaction between lamin A and both SREBP1a and 1c. A binding site for lamin A was identified in the N-terminal transcription factor domain of SREBP1, between residues 227 and 487. The binding of lamin A to SREBP1 was noticeably reduced by FPLD mutations. Interestingly, one EDMD-AD mutation also interfered with the interaction between lamin A and SREBP1. Whilst the physiological relevance of this interaction has yet to be elucidated, these data raise the intriguing possibility that fat loss seen in laminopathies may be caused, at least in part, by reduced binding of the adipocyte differentiation factor SREBP1 to lamin A.
Phase I and Pharmacologic Study of the Specific Matrix Metalloproteinase Inhibitor BAY 12-9566 on a Protracted Oral Daily Dosing Schedule in Patients With Solid Malignancies (2000)

The recommended dose of BAY 12-9566 for subsequent disease directed studies is 800 mg twice daily, which resulted in biologically relevant plasma C(ss) values and an acceptable toxicity profile. Although exploratory studies of MMPs in plasma were not revealing, it is conceivable that some tumor types and disease settings are more likely to produce more readily quantifiable levels of activated MMPs than others. Therefore, attempts to identify and quantify surrogate markers of MMP inhibitory effects should continue to be performed in disease-directed studies in more homogenous patient populations.