gebhart/patrepeval huggingface dataset:
Effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice: Murine Ortholog of the Fletcher Trait (2012)

Plasma kallikrein is a multifunctional serine protease involved in contact activation of coagulation. Deficiency in humans is characterised by prolonged activated partial thromboplastin time (aPTT); however, the balance between thrombosis and haemostasis is not fully understood. A study of plasma kallikrein-deficient mice revealed increased aPTT, without prolonged bleeding time. Prekallikrein antisense oligonucleotide (ASO) treatment in mice suggested potential for a positive therapeutic index. The current goal was to further define the role of plasma kallikrein in coagulation. Blood pressure and heart rate were normal in plasma kallikrein-deficient mice, and mice were completely protected from occlusion (100 ± 1.3% control flow) in 3.5% FeCl3 -induced arterial thrombosis versus heterozygotes (20 ± 11.4%) and wild-type littermates (8 ± 0%). Vessels occluded in 8/8 wild-type, 7/8 heterozygotes, and 0/8 knockouts. Anti-thrombotic protection was less pronounced in 5% FeCl3-induced arterial injury. Integrated blood flow was 8 ± 0% control in wild-type and heterozygotes, and significantly (p<0.01) improved to 43 ± 14.2% in knockouts. The number of vessels occluded was similar in all genotypes. Thrombus weight was significantly reduced in knockouts (-47%) and heterozygotes (-23%) versus wild-type in oxidative venous thrombosis. Average tail bleeding time increased modestly in knockout mice compared to wild-type. Average renal bleeding times were similar in all genotypes. These studies confirm and extend studies with prekallikrein ASO, and demonstrate that plasma kallikrein deletion prevents occlusive thrombus formation in mice with a minimal role in provoked bleeding. Additional support for the significance of the intrinsic pathway in the coagulation cascade is provided, as well as for a potential new anti-thrombotic approach.
Feedforward control of a closed-loop piezoelectric translation stage for atomic force microscope (2007)

Simple feedforward ideas are shown to lead to a nearly tenfold increase in the effective bandwidth of a closed-loop piezoelectric positioning stage used in scanning probe microscopy. If the desired control signal is known in advance, the feedforward filter can be acausal: the information about the future can be used to make the output of the stage have almost no phase lag with respect to the input. This keeps in register the images assembled from right and left scans. We discuss the design constraints imposed by the need for the feedforward filter to work robustly under a variety of circumstances. Because the feedforward needs only to modify the input signal, it can be added to any piezoelectric stage, whether closed or open loop.
Large current density from carbon nanotube field emitters (1999)

We observe that field emitters made from carbon nanotubes exhibit excellent macroscopic emission properties; they can operate at a very large current density, as high as 4 A/cm2. At electric fields as low as 4–7 V/μm, they emit technologically useful current densities of 10 mA/cm2. We show that the emission originates from nanotube ends with a characteristic structured ring pattern. The emission characteristics and durability of the carbon nanotube cold cathodes offer promising applications for vacuum microelectronic devices.
Metalorganic chemical vapor deposition of GaN on Si(111): Stress control and application to field-effect transistors (2001)

Two schemes of nucleation and growth of gallium nitride on Si(111) substrates are investigated and the structural and electrical properties of the resulting films are reported. Gallium nitride films grown using a 10–500 nm-thick AlN buffer layer deposited at high temperature (∼1050 °C) are found to be under 260–530 MPa of tensile stress and exhibit cracking, the origin of which is discussed. The threading dislocation density in these films increases with increasing AlN thickness, covering a range of 1.1 to &amp;gt;5.8×109 cm−2. Films grown using a thick, AlN-to-GaN graded buffer layer are found to be under compressive stress and are completely crack free. Heterojunction field effect transistors fabricated on such films result in well-defined saturation and pinch-off behavior with a saturated current of ∼525 mA/mm and a transconductance of ∼100 mS/mm in dc operation.
Lipopolysaccharide Activates Caspase-1 (Interleukin-1–Converting Enzyme) in Cultured Monocytic and Endothelial Cells (1998)

Interleukin-1 beta (IL-1 beta) is a pleiotropic proinflammatory cytokine. Mechanisms leading to its secretion include not only release of newly synthesized protein, but also cleavage of a preformed immature precursor protein into an active secretory form by the intracellular protease caspase-1 (formerly termed IL-1-converting enzyme [ICE]). Caspase-1 belongs to a rapidly growing family of cysteine proteases with substrate specificity for aspartate involved in cellular apoptosis. We have used an assay determining the caspase-1 activity based on cleavage of a fluorogenic peptide substrate to elucidate its role in lipopolysaccharide (LPS)-induced secretion of IL-1 beta. We show that LPS induces moderate caspase-1 activity in the monocytic cell line THP-1, in freshly isolated peripheral blood monocytes, and in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent fashion. Caspase-1 activation by LPS was associated with cleavage of the IL-1 beta precursor protein that was followed by release of the mature IL-1 beta protein in monocytic cells. In contrast, subsequent release of IL-1 beta by HUVECs was not significant. LPS-induced caspase-1 activation appeared not to result from modulation of caspase-1 transcript accumulation and inhibition of caspase-1 activity was accomplished by two specific inhibitors, YVAD-CHO and YVAD-CMK, capable of alleviating the release of mature IL-1 beta. Taken together, these results show that LPS moderately activates caspase-1 and that caspase-1 activation contributes to LPS induction of IL-1 beta secretion.
Conformation of Formacetal and 3‘-Thioformacetal Nucleotide Linkers and Stability of Their Antisense RNA·DNA Hybrid Duplexes (1997)

This study focuses on the characterization of the stability and conformation of the antisense oligodeoxyribonucleotides, d[CGCGTT x TTGCGC] [x = phosphodiester (-O-P(O)2-O-), formacetal (FMA, -O-CH2-O-), or 3'-thioformacetal linkage (TFMA, -S-CH2-O-)], in DNA.DNA and RNA.DNA duplexes (designated DI-III and RI-III, respectively). NMR analysis of two RNA.DNA hybrid duplexes containing a single FMA (the RII duplex) or 3'-TFMA (the RIII duplex) modification has been carried out. The conformations of these duplexes are compared with that of the unmodified hybrid duplex RI and with those of the DI-III duplexes. These analyses and comparisons indicate that the residue containing a 3'-FMA linker has a preference for the C2'-endo sugar pucker and adopts a canonical backbone conformation. In contrast, the residue containing a 3'-TFMA linker has a much increased preference for the C3'-endo sugar pucker and adopts different backbone conformations in the DNA.DNA and RNA.DNA duplexes. UV and NMR melting studies of the six duplexes demonstrate that the DNA.DNA duplexes are more stable than the corresponding RNA.DNA hybrid duplexes and that both FMA and 3'-TFMA destabilize the duplex. The 3'-TFMA modified duplex is less stable than the FMA duplex in the context of DNA.DNA recognition and is slightly more stable than the FMA hybrid duplex in the context of RNA.DNA recognition. These results suggest a correlation between the conformational preference of backbone modifications and the stability of antisense duplexes. The implications of these studies for optimized incorporation of FMA and 3'-TFMA linkers into oligonucleotides and for better design of antisense oligonucleotide analogs are discussed.
A coherent optically controlled phased array antenna system (1993)

A true-time delay, optically controlled phased array antenna system whereby a large number (100-2500) of antenna elements can receive a series of microwave delays via use of a coherent optical carrier signal is described. Both transmit and receive antenna arrays are described, and the signal-to-noise ratio for a 128 channel system is calculated to be approximately 40 dB with an optical link loss of only approximately 3 dB for a 1 GHz instantaneous bandwidth at a wavelength of lambda 1.55 mu m. It is shown that the use of coherent optically controlled phased array antennas provides improved controllability and immunity from noise and system losses over other architectures currently being investigated.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Cationization of protein antigens. III. Abrogation of oral tolerance. (1987)

The immunoregulatory effects of oral pretreatment of BDF1 mice with cationized bovine serum albumin (cBSA) and native bovine serum albumin (nBSA) have been compared. Oral administration of nBSA suppressed the antibody response to both forms of the antigen. In contrast, oral pretreatment with cBSA greatly enhanced the anti-BSA response in animals subsequently challenged i.p. with either the cationized or native form of the molecule. The enhancement observed with cBSA pretreatment was more pronounced than the suppression observed with the same amount and number of feedings of nBSA. As little as a single oral dose of 10 mg of cBSA produced a significant increase in antibody concentration. Cell transfer of spleen cells into irradiated syngeneic recipients demonstrated that both T cells and B cells were involved in the generation of the response, with a greater degree of enhancement provided by cBSA-pretreated T cells. These data extend our previous findings and demonstrate that administration of cBSA by a normally "tolerogenic" route results in enhancement rather than suppression of the immune response.
Releasing search queries and clicks privately (2009)

The question of how to publish an anonymized search log was brought to the forefront by a well-intentioned, but privacy-unaware AOL search log release. Since then a series of ad-hoc techniques have been proposed in the literature, though none are known to be provably private. In this paper, we take a major step towards a solution: we show how queries, clicks and their associated perturbed counts can be published in a manner that rigorously preserves privacy. Our algorithm is decidedly simple to state, but non-trivial to analyze. On the opposite side of privacy is the question of whether the data we can safely publish is of any use. Our findings offer a glimmer of hope: we demonstrate that a non-negligible fraction of queries and clicks can indeed be safely published via a collection of experiments on a real search log. In addition, we select an application, keyword generation, and show that the keyword suggestions generated from the perturbed data resemble those generated from the original data.
Mycoplasmas: molecular biology and pathogenesis. (1992)

Introduction Molecular architecture Metabolism and energy utilization Macromolecule biosynthesis and genetics Identification and treatment of pathogenic mycoplasmas Molecular basis of mycoplasma pathogenicity Evolution
Short-pulse generation by saturated KrF laser amplification of a steep Stokes pulse produced by two-step stimulated Brillouin scattering (2000)

We propose a new method for generating short laser pulses. It consists of generation of steep pulses and saturated amplification. A steep Stokes pulse created by two-step stimulated Brillouin scattering is amplified with a KrF laser under conditions of strong saturation. Pulse shortening by approximately 40% is achieved by amplification.
Methylation‐Specific PCR (1998)

Methylation-specific PCR is a rapid method used to determine the methylation status of DNA. Not only does methylation affect the expression of genes in normal cells, but it is now known that disease processes such as cancer can result in abnormal DNA methylation patterns. Methylation-specific PCR can be used to investigate imprinted genes, to assess human tumors for clonality by studying genes inactivated on the X chromosome, and to examine abnormally methylated CpG islands in neoplasia.
Nanopore-type black silicon anti-reflection layers fabricated by a one-step silver-assisted chemical etching (2013)

An effective and economical fabrication process for the synthesis of nanopore-type "black silicon", that significantly decreases reflectivity of silicon wafer surfaces, is reported using a room temperature one-step Ag-assisted chemical etching method. The effects on the surface morphology and the corresponding surface reflectivity of the concentration of the silver catalyst (500, 50, and 5 μM), the HF and H2O2 concentration in the silicon etchant, the HF : H2O2 ratio, and etching time have been investigated. Lower reflectivity is a balance between sufficient silver catalyst to create large numbers of nanopores on a silicon surface and excessive silver that brings deeply etched channels that would potentially short-circuit a solar cell junction. The lowest relative effective reflectivity (0.17% over a range of 300-1000 nm) occurs with a silver ion concentration of 50 μM, however, with the silver ion concentration decreases to 5 μM surfaces with a low relative effective reflectivity (2.60%) and a short nanopore length (<250 nm) can be obtained with 10 minute etching time, indicating that this method can be used as a simple (one-pot), low cost (low silver concentration), energy efficient (room temperature), method for the synthesis of anti-reflection layers for silicon-based solar cell applications.
A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins (2001)

In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D.
Signal Transduction of Mechanical Stimuli Is Dependent on Microfilament Integrity: Identification of Osteopontin as a Mechanically Induced Gene in Osteoblasts (1997)

Mechanical perturbation has been shown to modulate a wide variety of changes in second message signals and patterns of gene expression in osteoblasts. Embryonic chick osteoblasts were subjected to a dynamic spatially uniform biaxial strain (1.3% applied strain) at 0.25 Hz for a single 2-h period, and osteopontin (OPN), an Arg-Gly-Asp (RGD)-containing protein, was shown to be a mechanoresponsive gene. Expression of opn mRNA reached a maximal 4-fold increase 9 h after the end of the mechanical perturbation that was not inhibited by cycloheximide, thus demonstrating that mechanoinduction of opn expression is a primary response through the activation of pre-existing transcriptional factors. The signal transduction pathways, which mediated the increased expression of opn in response to mechanical stimuli, were shown to be dependent on the activation of a tyrosine kinase(s) and protein kinase A (PKA) or a PKA-like kinase. Selective inhibition of protein kinase C (PKC) had no effect on the mechanoinduction of osteopontin even though opn has been demonstrated to be an early response gene to phorbol 12-myristate 13-acetate (PMA) stimulation. Mechanotransduction was dependent on microfilament integrity since cytochalasin-D blocked the up-regulation of the opn expression; however, microfilament disruption had no effect on the PMA induction of the gene. The microtubule component of the cytoskeleton was not related to the mechanism of signal transduction involved in controlling opn expression in response to mechanical stimulation since colchicine did not block opn expression. Mechanical stimulus was shown to activate focal adhesion kinase (FAK), which specifically became associated with the cytoskeleton after mechanical perturbation, and its association with the cytoskeleton was dependent on tyrosine kinase activity. In conclusion, these results demonstrate that the signal transduction pathway for mechanical activation of opn is uniquely dependent on the structural integrity of the microfilament component of the cytoskeleton. In contrast, the PKC pathway, which also activates this gene in osteoblasts, acts independently of the cytoskeleton in the transduction of its activity.
Modular Aptameric Sensors (2004)

We report the first examples of modular aptameric sensors, which transduce recognition events into fluorescence changes through allosteric regulation of noncovalent interactions with a fluorophore. These sensors consist of: (a) a reporting domain, which signals the binding event of an analyte through binding to a fluorophore; (b) a recognition domain, which binds the analyte; and (c) a communication module, which serves as a conduit between recognition and signaling domains. We tested recognition regions specific for ATP, FMN, and theophylline in combinations with malachite green binding aptamer as a signaling domain. In each case, we were able to obtain a functional sensor capable of responding to an increase in analyte concentration with an increase in fluorescence. Similar constructs that consist only of natural RNA could be expressed in cells and used as sensors for intracellular imaging.
Unrestricted replication of human cytomegalovirus in hydrocortisone-treated macrophages (1991)

Monocytes differentiated in the presence of phytohemagglutinin P-stimulated T cells could be infected with human cytomegalovirus AD169 and produced low levels of infectious virus. Additional treatment with therapeutic levels of hydrocortisone resulted in a 10- to 100-fold increase in infectious virus production. Hydrocortisone-treated cells demonstrated immediate-early protein kinetics similar to that observed with human fibroblasts, whereas a delay of up to 24 h was observed with untreated cells. Late protein production was barely detectable by immunostaining without hydrocortisone treatment. In treated cells, however, late protein was detected and the levels correlated with the number of cells producing infectious virus. This system provides a model for human cytomegalovirus infection of macrophages in humans.
Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. (1994)

The c-erbB-2 proto-oncogene encodes a receptor tyrosine kinase (RTK) closely related to the epidermal growth factor receptor (EGFR). Overexpression of erbB-2 occurs in approximately 20% of human breast tumours, where increased expression correlates with poor patient prognosis. The EGFR is coupled to the Ras signalling pathway by interaction with the adaptor protein Grb2, and Sos, a Ras GDP-GTP exchange factor. In this study, activation of the erbB-2 receptor and its association with Grb2 and Sos was investigated in breast cancer cell lines which overexpress erbB-2. The receptor was found to be tyrosine phosphorylated in all cell lines in which it is overexpressed. Western blotting of Grb2 and Sos immuneprecipitates from such cells revealed co-precipitation of erbB-2, demonstrating association of the Grb2/Sos complex with erbB-2 in vivo. Furthermore, a fusion protein containing only the SH2 domain of Grb2 bound to erbB-2 immobilized on nitrocellulose, indicating that association with Grb2 is direct and mediated by the SH2 domain of Grb2. The degree of association between the erbB-2 receptor and Grb2 in vivo was related to erbB-2 overexpression, and MAP kinase, which functions downstream from Ras, displayed markedly increased activity in cell lines overexpressing erbB-2. These results demonstrate that erbB-2 is coupled to Ras signalling via the Grb2/Sos complex, and that overexpression of this receptor in breast cancer cells leads to amplification of the Ras signalling pathway.
Structural Basis of HIV-1 Neutralization by Affinity Matured Fabs Directed against the Internal Trimeric Coiled-Coil of gp41 (2010)

The conserved internal trimeric coiled-coil of the N-heptad repeat (N-HR) of HIV-1 gp41 is transiently exposed during the fusion process by forming a pre-hairpin intermediate, thus representing an attractive target for the design of fusion inhibitors and neutralizing antibodies. In previous studies we reported a series of broadly neutralizing mini-antibodies derived from a synthetic naïve human combinatorial antibody library by panning against a mimetic of the trimeric N-HR coiled coil, followed by affinity maturation using targeted diversification of the CDR-H2 loop. Here we report crystal structures of the N-HR mimetic 5-Helix with two Fabs that represent the extremes of this series: Fab 8066 is broadly neutralizing across a wide panel of B and C type HIV-1 viruses, whereas Fab 8062 is non-neutralizing. The crystal structures reveal important differences in the conformations of the CDR-H2 loops in the complexes that propagate into other regions of the antigen-antibody interface, and suggest that both neutralization properties and affinity for the target can be attributed, at least in part, to the differences in the interactions of the CDR-H2 loops with the antigen. Furthermore, modeling of the complex of an N-HR trimer with three Fabs suggests that the CDR-H2 loop may be involved in close intermolecular contacts between neighboring antibody molecules, and that such contacts may hinder the formation of complexes between the N-HR trimer and more than one antibody molecule depending on the conformation of the bound CDR-H2 loop which is defined by its interactions with antigen. Comparison with the crystal structure of the complex of 5-Helix with another neutralizing monoclonal antibody known as D5, derived using an entirely different antibody library and panning procedure, reveals remarkable convergence in the optimal sequence and conformation of the CDR-H2 loop.
Activation of Peroxisome Proliferator–Activated Receptor (PPAR)δ Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men (2007)

The PPARdelta agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle.