gebhart/patrepeval huggingface dataset:
Quantitative Analysis of the Targeting of Mannose‐Terminal Glucocerebrosidase (1996)

Gaucher's disease is an inherited lysosomal storage disorder that is caused by a deficiency of glucocerebrosidase. The resulting accumulation of the substrate glucosylceramide in macrophages of liver, spleen, and bone marrow causes severe clinical symptoms. Gaucher's disease is treated by intravenous administration of a modified glucocerebrosidase (Alglucerase), which has exposed mannose residues to promote uptake by target macrophages. To evaluate the effectiveness of the targeting of Alglucerase, we studied the fate of the enzyme in the rat. Intravenously injected Alglucerase was rapidly cleared from the circulation (half-life 2.0 +/- 0.5 min). The liver was the main site of uptake, with 65.6 +/- 1.2% of the dose present at 10 min after injection. Smaller amounts ( < 3% of the dose) were taken up by spleen and bone marrow. Previous injection with mannan substantially increased the plasma half-life of the enzyme (14.8 +/- 3.2 min versus 1.7 +/- 0.3 min in solvent-preinjected controls) and uptake of the enzyme by liver, spleen and bone marrow was reduced by > 90%. These findings indicate that the enzyme is taken up by these organs via mannose-specific receptors. Subcellular fractionation of the liver indicated that the enzyme is internalized and transported to the lysosomes. By isolating various liver cell types after injection of the Alglucerase, it was found that endothelial cells are the main site of uptake of the enzyme: 60.8 +/- 3.4% of the total liver uptake. Parenchymal and Kupffer cells were responsible for 31.0 +/- 3.1% and 8.2 +/- 0.7% of the hepatic uptake, respectively. We conclude that Alglucerase is rapidly cleared from the circulation by mannose-specific receptors in liver, spleen, and bone marrow. However, less than 10% of the enzyme taken up by the liver is accounted for by Kupffer cells, the hepatic target cells for therapeutic intervention. It is suggested that alterations of the formulation of the therapeutic enzyme may lead to a higher uptake by Kupffer cells and other macrophages, and thus to a more (cost)effective therapy of Gaucher's disease.
Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy (2007)

The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.
Developmentally regulated transcription of the four liver-specific genes for inter-α-inhibitor family in mouse (1993)

The inter-alpha-inhibitor family is composed of the plasma-protease inhibitors inter-alpha-inhibitor, pre-alpha-inhibitor and bikunin. Inter-alpha-inhibitor and pre-alpha-inhibitor are distinct assemblies of bikunin with distinct sets from three heavy (H) chains designated H1, H2 and H3. These H chains are encoded by a set of three evolutionarily related H genes, and bikunin by an alpha-1-microglobulin/bikunin precursor gene (AMBP). This precursor is cleaved to yield bikunin, a member of the Kunitz-type protease-inhibitor superfamily, and alpha-1-microglobulin, which belongs to the lipocalin superfamily. Northern-blot experiments with RNAs obtained from various tissues in fetal and in adult mice indicated that the transcription of the four AMBP and H genes is liver-restricted, although there is expression of H3 in brain. An analysis of the H1, H2, H3 and AMBP transcripts, as well as of transcripts for other control genes, in liver during development showed a progressive increase in the amounts of the H1, H2, H3 and AMBP RNAs, which all peak transiently at day 5 after birth. This was shown by a nuclear run-on experiment to originate from a change in transcription rate. The transient and postnatal increase in transcription could be explained neither by the liver-restricted expression nor by a common origin of these four genes, nor by a perinatal requirement for many lipocalins or protease inhibitors. This suggests that all four genes are perinatally triggered at the level of similar elements in their transcriptional regulatory regions, a conclusion strengthened by the weak expression of the four genes that is seen in a mutant mouse strain (albino) that is deficient in some liver-specific transcription factors.
Covalent stabilization of coiled coils of the HIV gp41 N region yields extremely potent and broad inhibitors of viral infection (2005)

Peptides from the N-heptad repeat region of the HIV gp41 protein can inhibit viral fusion, but their potency is limited by a low tendency to form a trimeric coiled-coil. Accordingly, stabilization of N peptides by fusion with the stable coiled-coil IZ yields nanomolar inhibitors [Eckert, D. M. & Kim, P. S. (2001) Proc. Natl. Acad. Sci. USA 98, 11187-11192]. Because the antiviral potency of IZN17 is limited by self-association equilibrium, we covalently stabilized the peptide by using interchain disulfide bonds. The resulting covalent trimer, (CCIZN17)3, has an extraordinary thermodynamic stability that translates into unprecedented antiviral potency: (CCIZN17)3 (i) inhibits fusion in a cell-cell fusion assay (IC50 = 260 pM); (ii) is the most potent fusion inhibitor described to date (IC50 = 40-380 pM) in a single-cycle infectivity assay against HIV(HXB2), HIV(NL4-3), and HIV(MN-1); (iii) efficiently neutralizes acute viral infection in peripheral blood mononuclear cells; and (iv) displays a broad antiviral profile, being able to neutralize 100% of a large panel of HIV isolates, including R5, X4, and R5/X4 strains. In all of these assays, the potency of N-peptide inhibitor (CCIZN17)3 was equal to or more than the C-peptide inhibitor in clinical use, DP178 (also known as Enfuvirtide and Fuzeon). More importantly, we show that the two inhibitors, which have different targets in gp41, synergize when used in combination. These features make (CCIZN17)3 an attractive lead to develop as an antiviral drug, alone or in combination with DP178, as well as a promising immunogen to elicit a fusion-blocking neutralizing antibody response.
Incidence of intimal proliferation and apoptosis following balloon angioplasty in an atherosclerotic rabbit model (2000)

Our data showed that significant changes in the occurrence of apoptosis are not involved in the regulation of cellular turnover during the examined time period after vessel wall injury. The lacking up-regulation of apoptosis in comparison to the increased cell proliferation in order to maintain the tissue balance is perhaps an important regulatory mechanism leading to intimal hyperplasia after vascular injury in this animal model. Overall, we suggest that there may be a delicate balance between cell proliferation and apoptosis in smooth muscle cells of the vessel wall, and only small shifts in this balance could account for both cellular accumulation in restenotic lesions as well as cell death in mature atheroma.
Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells bothin vitroandin vivo (2004)

These findings identify clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced lung cancer.
Phononic crystal with low filling fraction and absolute acoustic band gap in the audible frequency range: A theoretical and experimental study (2002)

The propagation of acoustic waves in a two-dimensional composite medium constituted of a square array of parallel copper cylinders in air is investigated both theoretically and experimentally. The band structure is calculated with the plane wave expansion (PWE) method by imposing the condition of elastic rigidity to the solid inclusions. The PWE results are then compared to the transmission coefficients computed with the finite difference time domain (FDTD) method for finite thickness composite samples. In the low frequency regime, the band structure calculations agree with the FDTD results indicating that the assumption of infinitely rigid inclusion retains the validity of the PWE results to this frequency domain. These calculations predict that this composite material possesses a large absolute forbidden band in the domain of the audible frequencies. The FDTD spectra reveal also that hollow and filled cylinders produce very similar sound transmission suggesting the possibility of realizing light, effective sonic insulators. Experimental measurements show that the transmission through an array of hollow Cu cylinders drops to noise level throughout frequency interval in good agreement with the calculated forbidden band.
P‐85: Simple Drive Scheme for Bistable Cholesteric LCDs (2001)

Abstract In this paper we discuss a new dynamic drive scheme for bistable reflective cholesteric liquid crystal displays with high multiplexing level. Only two voltage levels (U and 0) are used for the addressing in this drive scheme. Addressing speed is about the time of the fast transition of a cholesteric liquid crystal from the homeotropic state to the transient planar state per line. The maximum value of using voltage is slightly overtop the critical voltage of a cholesteric‐nematic transition. These facts make this drive scheme very perspective in application for such kind of displays.
Computational design of protein–ligand binding: Modifying the specificity of asparaginyl‐tRNA synthetase (2009)

A method for computational design of protein-ligand interactions is implemented and tested on the asparaginyl- and aspartyl-tRNA synthetase enzymes (AsnRS, AspRS). The substrate specificity of these enzymes is crucial for the accurate translation of the genetic code. The method relies on a molecular mechanics energy function and a simple, continuum electrostatic, implicit solvent model. As test calculations, we first compute AspRS-substrate binding free energy changes due to nine point mutations, for which experimental data are available; we also perform large-scale redesign of the entire active site of each enzyme (40 amino acids) and compare to experimental sequences. We then apply the method to engineer an increased binding of aspartyl-adenylate (AspAMP) into AsnRS. Mutants are obtained using several directed evolution protocols, where four or five amino acid positions in the active site are randomized. Promising mutants are subjected to molecular dynamics simulations; Poisson-Boltzmann calculations provide an estimate of the corresponding, AspAMP, binding free energy changes, relative to the native AsnRS. Several of the mutants are predicted to have an inverted binding specificity, preferring to bind AspAMP rather than the natural substrate, AsnAMP. The computed binding affinities are significantly weaker than the native, AsnRS:AsnAMP affinity, and in most cases, the active site structure is significantly changed, compared to the native complex. This almost certainly precludes catalytic activity. One of the designed sequences has a higher affinity and more native-like structure and may represent a valid candidate for Asp activity.
Temperature- and field-dependent electron and hole mobilities in polymer light-emitting diodes (1999)

We have studied the transport properties of electron- and hole-dominated MEH-PPV, poly(2-methoxy,5-(2′-ethyl-hexoxy)-p-phenylene vinylene), devices in the trap-free limit and have derived the temperature-dependent electron and hole mobilities (μ=μ0eγ√E) from the space-charge-limited behavior at high electric fields. Both the zero-field mobility μ0 and electric-field coefficient γ are temperature dependent with an activation energy of the hole and electron mobility of 0.38±0.02 and 0.34±0.02 eV, respectively. At 300 K, we find a zero-field mobility μ0 on the order of 1±0.5×10−7 cm2/V s and an electric-field coefficient γ of 4.8±0.3×10−4 (m/V)1/2 for holes. For electrons, we find a μ0 an order of magnitude below that for holes but a larger γ of 7.8±0.5×10−4 (m/V)1/2. Due to the stronger field dependence of the electron mobility, the electron and hole mobilities are comparable at working voltages in the trap-free limit, applicable to thin films of MEH-PPV.
Early Induction of Humoral and Cellular Immune Responses during ExperimentalMycobacterium aviumsubsp.paratuberculosisInfection of Calves (2003)

Johne's disease (paratuberculosis) of cattle is widespread and causes significant economic losses for producers due to decreased production and poor health of affected animals. The chronic nature of the disease and the lack of a reproducible model of infection hinder research efforts. In the present study, instillation of Mycobacterium avium subsp. paratuberculosis into the tonsillar crypts of neonatal calves resulted in peripheral colonization as detected by antemortem culture of feces and postmortem (320 days postchallenge) culture of intestinal tissues. Antigen-specific blastogenic, gamma interferon (IFN-gamma), and nitric oxide responses by blood mononuclear cells from infected calves exceeded prechallenge responses beginning 194 days postchallenge. Upon in vitro stimulation with paratuberculosis antigens, CD4(+) cells from infected calves proliferated, produced IFN-gamma, and increased expression of CD26 and CD45RO (indicative of an activated memory phenotype). Utilizing a lipoarabinomannan-based enzyme-linked immunosorbent assay, specific serum immunoglobulin was detected as early as 134 days postchallenge and generally increased after this time point. Two antigens of approximately 50 and approximately 60 kDa were particularly immunodominant early in infection, as shown by immunoblot with serum collected within 2 weeks postchallenge. Findings indicate that the intratonsillar inoculation route will prove useful as an experimental model for paratuberculosis infection. Additionally, this study confirms that mycobacteria-specific antibody is detectable early in the course of experimental Johne's disease, even preceding the development of specific cell-mediated responses.
Influence of substrate electrical bias on the growth of GaN in plasma-assisted epitaxy (1995)

A sample bias on the order of −15 V arises during electron cyclotron resonance plasma-assisted epitaxy of GaN on insulating substrates. In contrast, conducting substrates enable growth under zero or positive bias conditions. Surface morphology of GaN/Si(111) is progressively smoother with increasing bias (−10 to +10 V) for a microwave power of 30 W. Emission spectroscopy of the plasma suggests that both N and N+2 are produced from collisions involving N*2 and that for low power (10 W), the N and N+2 production is limited by the N*2 abundance. In contrast, at higher power (50 W), ion and atom production appears limited by the electron collision frequency. Electrostatic probe measurements near the growth stage indicate that the ion energy has a minimum of about 6 eV, attained at low plasma power or at medium power (30 W) with a positive substrate bias. Mg-doped films produced at 10 W and zero bias are highly resistive. p-n junction diodes formed by Si-doped GaN grown on Mg-doped GaN on p-type Si are operated at relatively low current densities of 100 A cm−2 and emit light near 2.5 eV at room temperature.
Hypertonic Saline Worsens Infarct Volume After Transient Focal Ischemia in Rats (2000)

These data demonstrate that hypernatremia resulting from postischemic HS infusion worsens cortical infarct volume in transient focal cerebral ischemia. The deleterious effect is not linked to exacerbation of delayed hypoperfusion during early reperfusion (6 hours); however, blood flow defects at later recovery time points remain to be excluded. These results may have implications for HS therapy in clinical ischemic stroke.
Toxicidade de amidas análogas à piperina a larvas de Ascia monuste orseis Godart (Lepidoptera: Pieridae) e Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) (2003)

Foi avaliada, no presente estudo, a toxicidade de amidas análogas à piperina utilizando-se larvas de 3º instar de Ascia monuste orseis Godart e Spodoptera frugiperda (J.E. Smith). Os bioensaios consistiram na aplicação tópica de 0.5 µl das seguintes amidas: N-isopentil-(3,4-metilenodioxifenil)-amida, N-isopropil-(3,4-metilenodioxifenil)-amida, N-hexil-3-(3,4-metilenodioxifenil)-amida e butóxido de piperonila. Os valores de DL50 (mg i.a./ mg larva) das amidas N-isopropil e N-hexil para A. monuste foram 0.278 e 0.004, respectivamente; para S. frugiperda foram: 1.359 e 0.613, respectivamente. O maior valor das inclinações das curvas de dose-resposta dentre os compostos, para ambas as espécies de inseto foi obtido para N-isopropil, o que indica maior homogeneidade de resposta a esse produto. N-isopropil foi o composto que se mostrou mais promissor como inseticida pois foi mais tóxico a ambas espécies-praga investigadas.
Human dendritic cells infected byListeria monocytogenes: induction of maturation, requirements for phagolysosomal escape and antigen presentation capacity (2000)

An important feature of microbial infections is the ability of the microorganisms to interfere with and modulate the induction of host immune reactions. However, little is known about the effects of broad host range pathogens such as Listeria monocytogenes on similar cell types in different hosts. Here we examine the effects of the human and animal pathogen L. monocytogenes on human dendritic cells (DC) since this type of cells is essential for the initiation of immune responses. Listeria are phagocytosed efficiently by immature human DC and the bacteria escape from the phagolysosome quickly. Lack of the pore-forming activity of listeriolysin, which was found to be essential for the vacuolar escape of this bacterium in other cell types, retarded but did not prevent egress from the vacuole. Treatment of cultures of immature DC with L. monocytogenes resulted in rapid changes in morphology and cellular constitution followed by maturation of the DC. This could be judged by the appearance of maturation-specific cell surface markers. Antigen presentation to CD4 T cells was apparently not impaired by the infection. These results are in clear contrast to results obtained previously in the mouse system (Guzman et al., Mol. Microbiol. 1996. 20: 119 - 126; Darji et al., Eur. J. Immunol. 1997. 27: 1696 - 1703.).
Reduced Lignin Content and Altered Lignin Composition in Transgenic Tobacco Down-Regulated in Expression of L-Phenylalanine Ammonia-Lyase or Cinnamate 4-Hydroxylase (1997)

We analyzed lignin content and composition in transgenic tobacco (Nicotiana tabacum) lines altered in the expression of the early phenylpropanoid biosynthetic enzymes L-phenylalanine ammonia-lyase and cinnamate 4-hydroxylase (C4H). The reduction of C4H activity by antisense expression or sense suppression resulted in reduced levels of Klason lignin, accompanied by a decreased syringyl/guaiacyl monomer ratio as determined by pyrolysis gas chromatography/mass spectrometry Similar reduction of lignin levels by down -regulation of L-phenylalanine ammonia-lyase, the enzyme preceding C4H in the central phenylpropanoid pathway, did not result in a decreased syringyl/guaiacyl ratio. Rather, analysis of lignin methoxyl content and pyrolysis suggested an increased syringyl/guaiacyl ratio. One possible explanation of these results is that monolignol biosynthesis from L-phenylalanine might occur by more than one route, even at the early stages of the core phenylpropanoid pathway, prior to the formation of specific monolignol precursors.
Analysis of ascorbic acid based black powder substitutes by high‐performance liquid chromatography/electrospray ionization quadrupole time‐of‐flight mass spectrometry (2010)

Black powder substitutes are an important sub-group of explosive propellants in the United States because they are readily accessible, and can be used as fillers for improvised explosive devices. Many brands of black powder substitutes incorporate an ascorbic acid fuel source with potassium nitrate (KNO(3)) and/or potassium perchlorate (KClO(4)) oxidizer(s). A gradient high-performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC/ESI-QToFMS) method has been developed for the analysis of both the organic and the inorganic constituents. The HPLC/ESI-QToFMS method was utilized to examine aqueous extracts of intact samples and post-burn residues from six different brands of ascorbic acid based powders. Aqueous extracts of the post-blast residues from two brands of ascorbic acid based propellant were also analyzed. The results showed that both the ascorbic acid fuel and the inorganic oxidizer(s) KClO(4) and/or KNO(3) were successfully detected via the [M-H](-) ion of ascorbic acid and the anions (ClO(4) (-) and NO(3) (-)) of the oxidizers. This method was proven to be a rapid and efficient procedure for the analysis of this class of explosives. The high mass resolution provided by the QToFMS instrument fulfills the degree of certainty required in a court of law.
Dependence of spin-transfer switching current on free layer thickness in Co–Fe–B∕MgO∕Co–Fe–B magnetic tunnel junctions (2006)

Magnetoresistance (MR) and spin-transfer switching (STS) properties were investigated in Co–Fe–B∕MgO∕Co–Fe–B magnetic tunnel junctions as a function of free layer thickness (dFree). The MR ratio was about 140% at dFree⩾2nm. It decreased to about 80% at dFree=1.5nm. Both switching currents and thermal stability were roughly proportional to dFree. The averaged intrinsic switching current density (Jc0av) was 1×107–2×107A∕cm2. The thermal stability of parallel magnetization state was greater than that of antiparallel state. The feasibility of the STS write scheme for nonvolatile magnetic random access memory was discussed.