gebhart/patrepeval huggingface dataset:
Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling (2004)

Sphingosine kinase (SK) 1 catalyzes the formation of the bioactive lipid sphingosine 1-phosphate, and has been implicated in several biological processes in mammalian cells, including enhanced proliferation, inhibition of apoptosis, and oncogenesis. Human SK (hSK) 1 possesses high instrinsic catalytic activity which can be further increased by a diverse array of cellular agonists. We have shown previously that this activation occurs as a direct consequence of extracellular signal-regulated kinase 1/2-mediated phosphorylation at Ser225, which not only increases catalytic activity, but is also necessary for agonist-induced translocation of hSK1 to the plasma membrane. In this study, we report that the oncogenic effects of overexpressed hSK1 are blocked by mutation of the phosphorylation site despite the phosphorylation-deficient form of the enzyme retaining full instrinsic catalytic activity. This indicates that oncogenic signaling by hSK1 relies on a phosphorylation-dependent function beyond increasing enzyme activity. We demonstrate, through constitutive localization of the phosphorylation-deficient form of hSK1 to the plasma membrane, that hSK1 translocation is the key effect of phosphorylation in oncogenic signaling by this enzyme. Thus, phosphorylation of hSK1 is essential for oncogenic signaling, and is brought about through phosphorylation-induced translocation of hSK1 to the plasma membrane, rather than from enhanced catalytic activity of this enzyme.
The role of nitric oxide in articular cartilage breakdown in osteoarthritis (1998)

It is increasingly appreciated that mediators typically associated with inflammatory arthritis, such as catabolic cytokines and nitric oxide, are produced by synovium and cartilage in osteoarthritis. The role that such mediators play in the progression of cartilage degradation in osteoarthritis is under intensive investigation. Nitric oxide is a highly reactive, cytotoxic free radical that has been implicated in tissue injury in a variety of diseases. Cartilage obtained from patients with osteoarthritis produces significant amounts of nitric oxide ex vivo, even in the absence of added stimuli such as interleukin-1 or lipopolysaccharide. In vitro, nitric oxide exerts detrimental effects on chondrocyte functions, including the inhibition of collagen and proteoglycan synthesis, enhanced apoptosis, and an inhibition of B1 integrin-dependent adhesion to the extra-cellular matrix. This paper reviews recent observations regarding the role of nitric oxide in osteoarthritis and presents evidence suggesting that the inhibition of nitric oxide production could be a desirable future therapeutic strategy.
VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature (2005)

Unlike during development, blood vessels in the adult are generally thought not to require VEGF for normal function. However, VEGF is a survival factor for many tumor vessels, and there are clues that some normal blood vessels may also depend on VEGF. In this study, we sought to identify which, if any, vascular beds in adult mice depend on VEGF for survival. Mice were treated with a small-molecule VEGF receptor (VEGFR) tyrosine kinase inhibitor or soluble VEGFRs for 1-3 wk. Blood vessels were assessed using immunohistochemistry or scanning or transmission electron microscopy. In a study of 17 normal organs after VEGF inhibition, we found significant capillary regression in pancreatic islets, thyroid, adrenal cortex, pituitary, choroid plexus, small-intestinal villi, and epididymal adipose tissue. The amount of regression was dose dependent and varied from organ to organ, with a maximum of 68% in thyroid, but was less in normal organs than in tumors in RIP-Tag2-transgenic mice or in Lewis lung carcinoma. VEGF-dependent capillaries were fenestrated, expressed high levels of both VEGFR-2 and VEGFR-3, and had normal pericyte coverage. Surviving capillaries in affected organs had fewer fenestrations and less VEGFR expression. All mice appeared healthy, but distinct physiological changes, including more efficient blood glucose handling, accompanied some regimens of VEGF inhibition. Strikingly, most capillaries in the thyroid grew back within 2 wk after cessation of treatment for 1 wk. Our findings of VEGF dependency of normal fenestrated capillaries and rapid regrowth after regression demonstrate the plasticity of the adult microvasculature.
Study of Thermal Aggregation of Oat Globulin by Laser Light Scattering (2004)

The heat-induced aggregation of oat globulin was studied using size-exclusion chromatography (SEC) combined with on-line multiangle laser light scattering (MALLS) and quasi-elastic light scattering (QELS). The unheated oat globulin exists as a mixture of hexamer (>95%), trimer, and dimer forms of hexamer. The molecular weight of the hexamer was estimated by MALLS to be 330 000, close to that deduced from the genomic cloned data of the acidic and basic polypeptides of oat globulin. From QELS measurements, it can be predicted that the hexamer exists as two annular trimeric rings, with a diameter of 11.8 nm, placed on top of each other, forming an oblate cylinder with a height of about 8.5 nm. Upon heating at 100 degrees C, the oat globulin hexamers and trimers were dissociated into monomers. The heat-denatured monomers, probably assuming an extended structure, were associated to form small aggregates, which were further aggregated to high molecular weight complexes. Upon further heating (60 min), the soluble aggregates were associated to form insoluble aggregates. Aggregation of oat globulin occurred at a much faster rate at 110 degrees C. The results indicate that the SEC-MALLS-QELS system is suitable for studying thermal aggregation of food proteins.
Rosuvastatin: a new inhibitor of HMG-CoA reductase for the treatment of dyslipidemia (2003)

Rosuvastatin (Crestor, AstraZeneca) is a synthetic statin that represents an advance on the pharmacologic and clinical properties of other agents in this class. Relative to other statins, rosuvastatin possesses a greater number of binding interactions with HMG-CoA reductase and has a high affinity for the active site of the enzyme. Rosuvastatin is relatively hydrophilic and is selectively taken up by, and active in, hepatic cells. Rosuvastatin has the longest terminal half-life of the statins and is only minimally metabolized by the cytochrome P450 (CYP 450) enzyme system with no significant involvement of the 3A4 enzyme. Consistent with this finding is the absence of clinically significant drug interactions between rosuvastatin and other drugs known to inhibit CYP 450 enzymes. In patients with hypercholesterolemia, rosuvastatin 10-40 mg has been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels by 52-63%, as well as increase high-density lipoprotein cholesterol (HDL-C) levels by up to 14% and reduce triglycerides (TG) by up to 28%. Studies have shown that rosuvastatin is superior to atorvastatin, simvastatin and pravastatin in reducing LDL-C and favorably modifying other components of the atherogenic lipid profile. The significant decreases in LDL-C with rosuvastatin treatment should help to improve attainment of lipid goals and reduce the requirement for dose titration. In addition, the effects of rosuvastatin on HDL-C and TG levels will be of benefit in treating patients with abnormalities such as mixed dyslipidemia and the metabolic syndrome. Rosuvastatin is well tolerated, with a safety profile comparable with that of other currently available statins.
Importance of Low-Range CAG Expansion and CAA Interruption in SCA2 Parkinsonism (2007)

This study demonstrates that SCA2 is one of the genetic causes of PD and MSA-P. All 3 patients had apparently sporadic disease, emphasizing the need to screen even in patients with nonfamilial disease. CAG repeats were in the low expansion range and interrupted by CAA in all patients in the low-range expansion. Therefore, accurate determination of CAG expansion and ATXN2 sequencing are warranted. [(123)I]FP-CIT SPECT and [(11)C]raclopride PET provide a useful way to evaluate the degree of nigrostriatal dopaminergic damage in SCA2-related parkinsonism and gene carriers.
Cytokine production in vitro and the lymphoproliferative defect of natural measles virus infection (1991)

In natural measles virus infection, evidence of intense immune system activation is present simultaneously with clinically relevant immune suppression. While evidence of activation is most prominent early in the disease, skin test responses and in vitro lymphoproliferation are depressed for weeks after the onset of the rash. It is not known whether the prolonged period of reduced immune responsiveness results from a single defect or a succession of different abnormalities. To gain further insight into measles-induced immune suppression we studied the production of soluble IL-2 receptor (sIL-2R), interferon-gamma (IFN-gamma), IL-1 beta, and tumor necrosis factor (TNF alpha) by peripheral blood mononuclear cells (PBMC) isolated from measles patients at various times after the onset of the rash. Studies included addition of supplemental recombinant IL-1 beta (rIL-1 beta) or recombinant IL-2 (rIL-2) or suppression of prostaglandin synthesis by indomethacin (IM). Proliferation in response to phytohemagglutin (PHA) was abnormal at all stages of disease. During the acute phase (first week after the onset of the rash) spontaneous production of sIL-2R was increased (76 +/- 54 vs. controls 4 +/- 4; P less than 0.03), suggesting in vivo T cell activation while PHA-induced sIL-2R was decreased (228 +/- 43 vs. control 582 +/- 127; P less than 0.002), suggesting that the capacity to produce IL-2 in response to mitogen was limited. Supplementation of PHA-stimulated cultures with rIL-2 improved but did not normalize both proliferation (58,600 +/- 4900 to 70,700 +/- 4400 vs. control 97,700 +/- 15,500; P less than 0.03) and sIL-2R levels (114 +/- 58 to 309 +/- 87 vs. control 582 +/- 127; P less than 0.003). Both spontaneous (25 +/- 18 vs. control 237 +/- 92; P less than 0.002) and PHA-induced (20 +/- 20 vs. control 604 +/- 129; P less than 0.004) TNF alpha levels were subnormal and were not improved with rIL-2, rIL-1 beta, or IM, suggesting a block in monocyte TNF alpha production. Spontaneous and PHA-induced IFN-gamma and IL-1 beta levels were normal. During the convalescent phase (greater than 2 weeks after the onset of the rash), spontaneous levels of sIL-2R were normal and PHA-induced levels were completely normalized with supplemental rIL-2 but proliferation remained below normal.(ABSTRACT TRUNCATED AT 400 WORDS)
Activation by nitric oxide of an oxidative-stress response that defends Escherichia coli against activated macrophages. (1993)

Nitric oxide is a free radical (NO) formed biologically through the oxidation of L-arginine by nitric oxide synthases. NO is produced transiently in mammalian cells for intercellular signaling and in copious quantities to cause cytostasis and cytotoxicity. In the latter situation, NO is a deliberate cytotoxic product of activated macrophages, along with other reactive oxygen species such as hydrogen peroxide (H2O2) and superoxide (O2-). Escherichia coli has a complex set of responses to H2O2 and O2- that involves approximately 80 inducible proteins; we wondered whether these bacteria might induce analogous defenses against nitric oxide. We show here that a multigene system controlled by the redox-sensitive transcriptional regulator SoxR is activated by NO in vivo. This induction confers bacterial resistance to activated murine macrophages with kinetics that parallel the production of NO by these cells. Elimination of specific SoxR-regulated genes diminishes the resistance of these bacteria to the cytotoxic macrophages. The required functions include manganese-containing superoxide dismutase, endonuclease IV (a DNA-repair enzyme for oxidative damage), and micF, an antisense regulator of the outer membrane porin OmpF. These results demonstrate that SoxR is a sensor for cellular exposure to NO, and that the soxRS response system may contribute to bacterial virulence.
Surveillance for Lyme disease--United States, 1992-2006. (2008)

The results presented in this report underscore the continued emergence of Lyme disease and the need for tick avoidance and early treatment interventions. Public health practitioners can use the data presented in this report to target prevention campaigns to populations with increasing incidence (i.e., children and young males).
Expression in recombinant vaccinia virus of the equine herpesvirus 1 gene encoding glycoprotein gp13 and protection of immunized animals (1989)

The equine herpesvirus 1 (EHV-1) gene encoding glycoprotein 13 (gp13) was cloned into the hemagglutinin (HA) locus of vaccinia virus (Copenhagen strain). Expression of the gp13 gene was driven by the early/late vaccinia virus H6 promoter. Metabolically radiolabeled polypeptides of approximately 47 and 44 kilodaltons and 90 kilodaltons (glycosylated form) were precipitated with both polyclonal and gp13-specific monoclonal antibodies. Presentation of gp13 on the cytoplasmic membrane of cells infected with the recombinant gp13 vaccinia virus was demonstrated by immunofluorescence of unfixed cells. Inoculation of the recombinant gp13 vaccinia virus into guinea pigs induced neutralizing antibodies to both EHV-1 and vaccinia virus. Hamsters vaccinated with the recombinant gp13 vaccinia virus survived a lethal challenge with the hamster-adapted Kentucky strain of EHV-1. These results indicate that expression in vaccinia virus vectors of EHV-1 gp13, the glycoprotein homolog of herpes simplex virus gC-1 and gC-2, pseudorabies virus gIII, and the varicella-zoster virus gpV may provide useful vaccine candidates for equine herpesvirus infections.
Vanilloid (Capsaicin) Receptors in Health and Disease (2002)

The cloned vanilloid (capsaicin) receptor subtype 1 (VR1) integrates multiple noxious stimuli on peripheral terminals of primary sensory neurons. The initial excitation of these neurons is followed by a lasting refractory state, traditionally termed desensitization, that has clear therapeutic potential. Capsaicin is used to relieve neuropathic pain, uremic pruritus, and bladder overactivity. The ultrapotent vanilloid resiniferatoxin, now in phase 2 clinical trials, has improved tolerability. A less recognized human exposure to high capsaicin concentrations may occur by pepper sprays used in law enforcement. Evidence is mounting that VR1 expression is not restricted to sensory neurons. From the olfactory bulb to the cerebellum, VR1-expressing neurons are present in a number of brain nuclei, where they might be activated by anandamide. VR1 presence also was demonstrated in nonneuronal tissues. These discoveries place VR1 in a much broader perspective than pain perception and enhance the potential for unforeseen side effects, especially following prolonged vanilloid therapy. The expression of VR1 is plastic and down-regulated during vanilloid therapy, which might have a pivotal role in desensitization. Good evidence suggests altered VR1 expression in various disease states. This recognition not only may provide novel insights into pathogenesis but also may prove useful in diagnosis.
All fiber 2 x 2 polarization insensitive switch (1997)

We report the development of a polarization insensitive all fiber 2×2 acoustooptic switch based on twisting the waist of a null taper coupler. The polarization insensitivity is better than 0.2 dB, the device requires a drive power of <1 mW, and exhibits a switching time of <50 μs and insertion loss of 0.1 dB.
Extensive splenic B cell activation in IgMtransgenic mice (1990)

Two lines of IgM-transgenic mice were analyzed for the state of activation of their splenic compartment, with regard to the frequency of large cells in the different lymphoid subpopulations, and to the isotype distribution of background plasma cells. We observed an extensive B cell activation preferentially involving B lymphocytes co-expressing transgenic and endogenous IgM (IgD), and resulting in massive immunoglobulin class switch. Nearly all splenic plasma cells contain endogenous immunoglobulins, with frequencies of IgG and IgA plasma cells significantly higher than in normal mice. There are virtually no plasma cells that produce only the transgenic IgM. Moreover, only a proportion of plasma cells producing endogenous immunoglobulins co-express the transgenic product. In addition to these observations that apply to both transgenic lines, differences were found between the two lines concerning the quantitative expression of the transgenic IgM, the frequency of cells expressing the transgene and the magnitude of switch. These data are indicative of the complexity of the IgM-transgenic mouse model, in which the phenomenology may depend on the transgene insertional position, on B cell physiology and on immunological mechanisms of recognition, induction and regulation.
Major histocompatibility complex‐restricted cellular interactions determining B cell activation (1982)

Abstract Requirements for antigen‐ and major histocompatibility complex (MHC)‐restricted cellular interactions for an in vitro secondary anti‐2,4‐dinitrophenyl (DNP) response, as well as the accompanying polyspecific immune response, are assessed. Induction of the polyspecific B cell response requires only the MHC‐restricted, antigen‐specific activation of helper T cells. Once the latter is accomplished, the polyspecific Ig response is not limited by B cell MHC. In contrast, MHC‐restricted T helper cell activation is not sufficient for the activation of long‐term primed, DNP‐specific B cells. Their activation also depends on antigen presentation in conditions of linked recognition, i.e. , hapten covalently linked to carrier, as well as recognition of B cell MHC by helper T cells. Moreover, the results demonstrate that the MHC‐restricted T‐macrophage and T‐B cell interactions are independent and rule out the involvement of MHC‐restricted 3 cell‐MHC, interactions. The differential induction requirements for DNP‐specific and polyspecific B cell responses are considered to reflect different states of B cell activation. When DNP‐primed B cells are derived from animals recently challenged with antigen, their induction requirements are identical to those for polyspecific B cells. The requirements for linked recognition and syngenicity with helper T cells are lost and their amplification is mediated by antigen‐specific, MHC‐restricted helper T cell activation (T cell‐mac‐rophage) alone. Activation requirements limiting the induction of a bystander erythrocyte response mediated by protein‐specific T cells (keyhole limpet hemocyanin) are considered within this context. At low keyhole limpet hemocyanin concentrations, induction requirements for sheep red blood cell‐specific bystander B cells parallel those for polyspecific B cells and recently boosted DNP‐specific B cells. However, at high antigen concentrations, bystander B cells syngeneic to T helper cells are preferentially induced. This latter phenomenon is considered to reflect antigen presentation by B cells. We conclude that the differing requirements for MHC‐restricted T‐macrophage and T‐B cell interactions in different B cell responses depend primarily on the pre‐existing state of B cell activation at the time of challenge.
Production of Biologically Active Mature Brain-derived Neurotrophic Factor inEscherichia coli (1995)

A gene coding for a brain-derived neurotrophic factor (BDNF) obtained from rat BDNF cDNA was used to construct an expression plasmid, pTRSBDNF. It contained a BDNF gene that was fused, in frame, to a region encoding the beta-lactamase signal peptide. The E. coli HB101 harboring pTRSBDNF produced 18 mg/liter of mature protein. The E. coli cells produced a larger amount of BDNF than that of human nerve growth factor (hNGF), which was produced using the same expression system. The E. coli cells harboring pTRSBDNF were sonicated and centrifuged to obtain a supernatant and precipitate. The BDNF purified from the supernatant containing 20% of the total BDNF had high biological activity (EC50 of 30 pg/ml) against neurons of chick dorsal root ganglia. On the other hand, the BDNF purified from the precipitate had low biological activity (EC50 of 2 ng/ml) and incorrect disulfide bonds.
Catalysis of atomic hydrogen to new hydrides as a new power source (2007)

Having the potential for a clean new energy source, rt-plasmas of certain catalysts (Sr+, Ar+, K) with H formed at extraordinary low field strengths of about 1?2 V/cm. Time-dependent, extraordinarily fast H (25 eV), an excess power of 20 mW ? cm−3, and characteristic K3+ emission confirmed the resonant nonradiative energy transfer of 3 ? 27.2 eV from atomic hydrogen to K as the rt-plasma catalyst. The predicted very stable novel hydride ion H−(1/4) with fractional principal quantum number p = 4 was observed spectroscopically at 110 nm corresponding to its predicted binding energy of 11.2 eV that further matched the 1H MAS NMR spectrum having an extraordinary upfield-shifted peak at ?4.4 ppm with the elimination of any known assignment by FTIR.
Sustainable Systemic Delivery via a Single Injection of Lentivirus into Human Skin Tissue (2001)

The skin offers a tissue site accessible for delivery of gene-based therapeutics. To develop the capability for sustained systemic polypeptide delivery via cutaneous gene transfer, we generated and injected pseudotyped HIV-1 lentiviral vectors intradermally at a range of doses into human skin grafted on immune-deficient mice. Unlike Moloney murine leukemia virus (MLV)-based retrovectors, which failed to achieve detectable cutaneous gene transfer by this approach, lentivectors effectively targeted all major cell types within human skin tissue, including fibroblasts, endothelial cells, keratinocytes, and macrophages. After a single injection, lentivectors encoding human erythropoietin (EPO) produced dose-dependent increases in serum human EPO levels and hematocrit that increased rapidly within one month and remained stable subsequently. Delivered gene expression was confined locally at the injection site. Excision of engineered skin led to rapid and complete loss of human EPO in the bloodstream, confirming that systemic EPO delivery was entirely due to lentiviral targeting of cells within skin rather than via spread of the injected vector to visceral tissues. These findings indicate that the skin can sustain dosed systemic delivery of therapeutic polypeptides via direct lentivector injection and thus provide an accessible and reversible approach for gene-based delivery to the bloodstream.
PET imaging of GRP receptor expression in prostate cancer. (2004)

In the United States alone, 1 in 6 men will be diagnosed with prostate cancer over the course of their lifetimes, with 31,000 dying each year from the disease. Imaging prostate cancer remains a major challenge in nuclear medicine. 18F-FDG, the most commonly used radiotracer for the detection of
Fixed-Gap Tunnel Junction for Reading DNA Nucleotides (2014)

Previous measurements of the electronic conductance of DNA nucleotides or amino acids have used tunnel junctions in which the gap is mechanically adjusted, such as scanning tunneling microscopes or mechanically controllable break junctions. Fixed-junction devices have, at best, detected the passage of whole DNA molecules without yielding chemical information. Here, we report on a layered tunnel junction in which the tunnel gap is defined by a dielectric layer, deposited by atomic layer deposition. Reactive ion etching is used to drill a hole through the layers so that the tunnel junction can be exposed to molecules in solution. When the metal electrodes are functionalized with recognition molecules that capture DNA nucleotides via hydrogen bonds, the identities of the individual nucleotides are revealed by characteristic features of the fluctuating tunnel current associated with single-molecule binding events.