gebhart/patrepeval huggingface dataset:
Clearance of Amyloid-&#946; Peptide Across the Blood-Brain Barrier: Implication for Therapies in Alzheimers Disease (2009)

The main receptors for amyloid-beta peptide (Abeta) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE), respectively. In normal human plasma a soluble form of LRP1 (sLRP1) is a major endogenous brain Abeta 'sinker' that sequesters some 70 to 90 % of plasma Abeta peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind Abeta are reduced which increases free Abeta fraction in plasma. This in turn may increase brain Abeta burden through decreased Abeta efflux and/or increased Abeta influx across the BBB. In Abeta immunotherapy, anti-Abeta antibody sequestration of plasma Abeta enhances the peripheral Abeta 'sink action'. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Abeta antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Abeta antibody/Abeta immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Abeta burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Abeta is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptor-associated protein (RAP) that does not directly bind Abeta. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Abeta 'sink' action, hold potential to reduce brain Abeta and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.
An Internet-based platform for testing generation scheduling auctions (2002)

The paper describes the uses and architecture of a network-centered computing-rich software platform called PowerWeb. PowerWeb was designed and built as a simulation environment for experimentally testing various power exchange auction markets through tournaments. It is designed to host simulations of a competitive "day-ahead" electric energy market in the content of a restructured electric power industry. The PowerWeb environment is meant to be flexible so as to accommodate different "rules of the game". The authors describe its interactive, distributed and Web-based character.
Caffeine and Related Methylxanthines: Possible Naturally Occurring Pesticides (1984)

Natural and synthetic methylxanthines inhibit insect feeding and are pesticidal at concentrations known to occur in plants. These effects are due primarily to inhibition of phosphodiesterase activity and to an increase in intracellular cyclic adenosine monophosphate. At lower concentrations, methylxanthines are potent synergists of other pesticides known to activate adenylate cyclase in insects. These data suggest that methylxanthines may function as natural insecticides and that phosphodiesterase inhibitors, alone or in combination with other compounds, may be useful in insect control.
Positive regulation of the peroxisomal β‐oxidation pathway by fatty acids through activation of peroxisome proliferator‐activated receptors (PPAR) (1993)

Peroxisome proliferators regulate the transcription of genes by activating ligand-dependent transcription factors, which, due to their structure and function, can be assigned to the superfamily of nuclear hormone receptors. Three such peroxisome proliferator-activated receptors (PPAR alpha, beta, and gamma) have been cloned in Xenopus laevis. Their mRNAs are expressed differentially; xPPAR alpha and beta but not xPPAR gamma are expressed in oocytes and embryos. In the adult, expression of xPPAR alpha and beta appears to be ubiquitous, and xPPAR gamma is mainly observed in adipose tissue and kidney. Immunocytochemical analysis revealed that PPARs are nuclear proteins, and that their cytoplasmic-nuclear translocation is independent of exogenous activators. A target gene of PPARs is the gene encoding acyl-CoA oxidase (ACO), which catalyzes the rate-limiting step in the peroxisomal beta-oxidation of fatty acids. A peroxisome proliferator response element (PPRE), to which PPARs bind, has been identified within the promoter of the ACO gene. Besides the known xenobiotic activators of PPARs, such as hypolipidemic drugs, natural activators have been identified. Polyunsaturated fatty acids at physiological concentrations are efficient activators of PPARs, and 5,8,11,14-eicosatetraynoic acid (ETYA), which is the alkyne homolog of arachidonic acid, is the most potent activator of xPPAR alpha described to date. Taken together, our data suggest that PPARs have an important role in lipid metabolism.
Pancreas and Islet Transplantation (1995)

Transplantation of either pancreas or islet tissue is the only available therapy for type I diabetes that establishes normoglycemia and restores physiologic insulin secretion. This restoration of eu-glycemia may, in turn, be associated with beneficial effects on secondary diabetic complications. Despite increasing success rates and the obvious benefits for carbohydrate metabolism and diabetic complications, pancreas and islet transplantation are not yet considered standard therapy for patients with diabetes. The limitations of pancreas and islet transplantation include the morbidity and mortality associated with the surgery, the need for lifelong immunosuppressive therapy, and the significant financial costs of the procedure. In contrast to these limitations, successful pancreas transplantation establishes sustained normoglycemia without the need for exogenous insulin, restores glucose-responsive insulin secretion and glucagon response to hypoglycemia, and improves quality of life. For pancreas transplantation to achieve the clinical acceptability of other forms of transplantation, clear advantages over exogenous insulin therapy must be demonstrated. This can only happen with the completion of well-controlled comparative studies that permit a clearer understanding of the benefits and risks of pancreas transplantation in the treatment of type I diabetic patients.
Role of mesenchymal stem cells in regenerative medicine: application to bone and cartilage repair (2008)

MSC can migrate to injured tissues and some of their reparative properties are mediated by paracrine mechanisms including their immunomodulatory actions. MSC possess a critical potential in regenerative medicine for the treatment of skeletal diseases, such as osteoarthritis or fracture healing failure, where treatments are partially effective or palliative.
Inhibition of Factor VIIa-Tissue Factor Coagulation Activity by a Hybrid Protein (1990)

Lipoprotein-associated coagulation inhibitor (LACI) appears to inhibit tissue factor (TF)-induced blood coagulation by forming a quaternary inhibitory complex containing factor Xa, LACI, factor VIIa, and TF. A genetically engineered hybrid protein consisting of the light chain of factor Xa and the first Kunitz-type inhibitor domain of LACI is shown to directly inhibit the activity of the factor VIIa-TF catalytic complex. Unlike inhibition of factor VIIa-TF activity by native LACI, inhibition by the hybrid protein is not dependent on factor Xa. In an assay of TF-induced coagulation, 50% TF inhibition occurs with hybrid protein at 35 nanograms per milliliter, whereas LACI at 2.5 micrograms per milliliter is required for an equivalent effect. gamma-Carboxylation of glutamic acid residues in the factor Xa light chain portion of the hybrid protein is required for inhibitory activity, indicating that the first Kunitz-type domain of LACI alone is not sufficient for inhibition of factor VIIa-TF.
Transition-metal contacts to atomically clean silicon (1976)

Atomically clean silicon surfaces have been produced by cleaving n-type silicon single crystals on a (111) plane in UHV conditions, and their workfunction has been measured. Transition metals of the 3d and 5d series have been evaporated on these surfaces and their workfunctions as well as the barrier heights of the resulting intimate metal-silicon contacts have also been measured without breaking the ultra-high vacuum. No simple relationship of the type predicted by the Schottky theory exists between barrier heights and metal workfunctions, and in the case of the sequence Fe-Co-Ni the barrier height actually decreases as the workfunction increases.
In VivoDelivery of a Bcl-xL Fusion Protein Containing the TAT Protein Transduction Domain Protects against Ischemic Brain Injury and Neuronal Apoptosis (2002)

Bcl-xL is a well characterized death-suppressing molecule of the Bcl-2 family. Bcl-xL is expressed in embryonic and adult neurons of the CNS and may play a critical role in preventing neuronal apoptosis that occurs during brain development or results from diverse pathologic stimuli, including cerebral ischemia. In this study, we used a novel approach to study the potential neuroprotective effect of Bcl-xL as a therapeutic agent in the murine model of focal ischemia/reperfusion. We created a Bcl-xL fusion protein, designated as PTD-HA-Bcl-xL, which contains the protein transduction domain (PTD) derived from the human immunodeficiency TAT protein. We demonstrated that this fusion protein is highly efficient in transducing into primary neurons in cultures and potently inhibited staurosporin-induced neuronal apoptosis. Furthermore, intraperitoneal injection of PTD-HA-Bcl-xL into mice resulted in robust protein transduction in neurons in various brain regions within 1-2 hr, and decreased cerebral infarction (up to approximately 40%) in a dose-dependent manner, as determined at 3 d after 90 min of focal ischemia. PTD-HA-Bcl-xL was effective even when it was administered after the completion of ischemia (up to 45 min), and the protective effect was independent of the changes in cerebral blood flow or other physiological parameters. Finally, as shown by immunohistochemistry, Western blotting, and substrate-cleavage assays, PTD-HA-Bcl-xL attenuated ischemia-induced caspase-3 activation in ischemic neurons. These results thus confirm the neuroprotective effect of Bcl-xL against ischemic brain injury and provide the first evidence that the PTD can be used to efficiently transduce a biologically active neuroprotectant in experimental cerebral ischemia.
Selective stimulation of prostatic carcinoma cell proliferation by transferrin. (1992)

Aggressive prostatic carcinomas most frequently metastasize to the skeletal system. We have previously shown that cultured human prostatic carcinoma cells are highly responsive to growth factors found in human bone marrow. To identify the factor(s) responsible for the increased prostatic carcinoma cell proliferation, we fractionated crude bone marrow preparations by using hydroxylapatite HPLC. The major activity peak contained two high molecular weight bands (M(r) = 80,000 and 69,000) that cross-reacted with antibodies to human transferrin and serum albumin, respectively. Bone marrow transferrin, purified to apparent homogeneity by using DEAE-Affi-Gel Blue chromatography, anti-transferrin affinity chromatography, and hydroxylapatite HPLC, markedly stimulated prostatic carcinoma cell proliferation, whereas human serum albumin showed no significant growth factor activity. Marrow preparations, depleted of transferrin by passage over an anti-transferrin affinity column, lost greater than 90% of their proliferative activity. In contrast to the response observed with the prostatic carcinoma cell lines, a variety of human malignant cell lines, derived from other primary sites and metastatic to sites other than bone marrow, showed a reduced response to purified marrow-derived transferrin. These results suggest that rapid growth of human prostatic carcinoma metastases in spinal bone may result from a combination of conditions that include (i) drainage of prostatic carcinoma cells into the paravertebral circulation, (ii) high concentrations of available transferrin in bone marrow, and (iii) increased sensitivity of prostatic carcinoma cells to the mitogenic activity of transferrin.
The use of thymidine analogs to improve the replication of an extra DNA base pair: a synthetic biological system (2005)

Synthetic biology based on a six-letter genetic alphabet that includes the two non-standard nucleobases isoguanine (isoG) and isocytosine (isoC), as well as the standard A, T, G and C, is known to suffer as a consequence of a minor tautomeric form of isoguanine that pairs with thymine, and therefore leads to infidelity during repeated cycles of the PCR. Reported here is a solution to this problem. The solution replaces thymidine triphosphate by 2-thiothymidine triphosphate (2-thioTTP). Because of the bulk and hydrogen bonding properties of the thione unit in 2-thioT, 2-thioT does not mispair effectively with the minor tautomer of isoG. To test whether this might allow PCR amplification of a six-letter artificially expanded genetic information system, we examined the relative rates of misincorporation of 2-thioTTP and TTP opposite isoG using affinity electrophoresis. The concentrations of isoCTP and 2-thioTTP were optimal to best support PCR amplification using thermostable polymerases of a six-letter alphabet that includes the isoC-isoG pair. The fidelity-per-round of amplification was found to be 98% in trial PCRs with this six-letter DNA alphabet. The analogous PCR employing TTP had a fidelity-per-round of only 93%. Thus, the A, 2-thioT, G, C, isoC, isoG alphabet is an artificial genetic system capable of Darwinian evolution.
Bertrand Competition (2008)

This article presents the classic Bertrand model of oligopolistic price competition and shows how alternative assumptions on economic primitives – such as the structure of demand and cost functions, tie-breaking rules, and product differentiation – shape Nash equilibrium prices and profits. We also discuss the related Bertrand–Edgeworth model of price competition in which consumers may be rationed – either strategically or due to capacity constraints – and illustrate how alternative rationing rules influence equilibrium.
Spatial-frequency spectrum of patterns changes the visibility of spatial-phase differences (1985)

This study showed that spatial-frequency components over a 4-octave range affected the visibility of spatial-phase differences. Contrast thresholds were measured for discrimination between two (+45- and -45-deg) spatial phases of a sinusoidal test grating added to a background grating. The background could contain one or several sinusoidal components, all in 0-deg phase. Phase differences between the test and the background were visible at lower constrasts (1) when test and background frequencies were harmonically related than when they were not, (2) when test and background frequencies were within 1 octave than when they were farther apart, (3) when the fundamental frequency of the background was low than when it was high, and (4) for some discriminations more than for others, after practice. The visibility of phase differences was not affected by additional components in the background if the fundamental and difference frequencies of the background remained unchanged. Observers' reports of their strategies gave information about the types of attentive processing that were used to discriminate phase differences. Attentive processing facilitated phase discrimination for multifrequency gratings spanning a much wider range of spatial frequencies than would be possible by using only local preattentive processing. These results were consistent with the visibility of phase differences being processed by some combination of even- and odd-symmetric simple cells tuned to a wide range of different spatial frequencies.
PD‐1 signaling in primary T cells (2009)

Programmed death-1 (PD-1) is a cell surface molecule that regulates the adaptive immune response. Engagement of PD-1 by its ligands PD-L1 or PD-L2 transduces a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function. While a great deal is known concerning the biologic roles PD-1 plays in regulating the primary immune response and in T-cell exhaustion, comparatively little is known regarding how PD-1 ligation alters signaling pathways. PD-1 ligation is known to inhibit membrane-proximal T-cell signaling events, while ligation of the related inhibitory molecule cytotoxic T-lymphocyte antigen-4 appears to target more downstream signaling pathways. A major obstacle to an in-depth understanding of PD-1 signaling is the lack of physiologic models in which to study signal transduction. This review focuses on: (i) signaling pathways altered by PD-1 ligation, (ii) factors recruited upon PD-1 phosphorylation, and (iii) exploring the hypothesis that PD-1 ligation induces distinct signals during various stages of immune-cell differentiation. Lastly, we describe models to dissect the function of the PD-1 cytoplasmic tail using primary cells in the absence of agonist antibodies.
Osteopenia and Bone Fractures in a Man With Anorexia Nervosa and Hypogonadism (1986)

Women with anorexia nervosa have reduced skeletal mass. Both anorexia and osteopenia are less common in men. We describe a 22-year-old man with anorexia nervosa and severe osteopenia involving both cortical and trabecular bone who developed a pelvic fracture and multiple vertebral compression fractures. He was found to have secondary hypogonadotropic hypogonadism that was reversible with weight gain. This case illustrates the need to consider osteopenia as a potential complication of anorexia nervosa in males as well as females.
Effect of DNA methylation on dynamic properties of the helix and nuclear protein binding in the H-ras promoter (1993)

The regulatory role of cytosine methylation in the genome is incompletely understood despite considerable evidence that it is often associated with the repression of specific gene expression (Doerfler, 1983; Cedar, 1988). The emerging data on distribution of the CpG dinucleotide, which is the major target for cytosine methylation, is thought to reflect a basic type of organization of regulatory sequences in the genome. This dinucleotide is severely underrepresented in bulk vertebrate DNA; but it occurs at the frequency predicted by base composition in CpG islands (Bird, 1986). It is estimated that from 15% to 30% of known genes contain CpG islands. Although they can be found in the 3′ flanking region and in the transcriptional unit of associated genes, a large proportion occur in the 5′ flanking regions which overlap with promoter regions (Gardiner-Garden and Frommer, 1987). Since CpG island sequences are potentially targets for methylation, it is not clear why some of these regions cannot be methylated in the cell (Lock et al., 1986; Dobkin et al., 1989; Szyf et al., 1990) and if, functionally, cytosine methylation of CpG islands in promoter region inactivates transcription.
Development and characterization of [123I]iodotiagabine for in-vivo GABA-transporter imaging (2012)

The increased knowledge of molecular changes associated with different neurological disorders calls for the development of novel radioligands. Tiagabine (Gabitril) is an anticonvulsive drug that binds selectively to GABA transporter-1 and thereby inhibits GABA uptake. As radioligands for in-vivo imaging of the GABA transporter are not yet available, we radiolabelled tiagabine and assessed its efficacy for in-vivo imaging of these transporters. Tiagabine was first brominated at its vinylic part, which was then exchanged with I. Next, anaesthetized rats received a bolus injection of [I]iodotiagabine in their tail vein, which was immediately followed by acquisition of planar and high-resolution micro-single-photon emission computed tomography (SPECT) images of the total body with special focus on the brain. Uptake in anatomical regions was assessed by coregistration of micro-SPECT with micro-CT images. Tiagabine labelling with I resulted in 50% yield and 99.7% radiochemical purity. Within 3 h after injection, SPECT demonstrated an increased signal-to-background ratio in the nasal mucosa and/or the Harderian glands but not in the brain. In addition we observed an increased signal-to-background ratio in organs such as the thyroid, heart, liver, kidney and bladder. More than 99% pure I-labelled tiagabine can be obtained and applied in animal micro-SPECT studies. However, this new radioligand is not taken up sufficiently by the brain and therefore cannot be used to successfully detect cerebral GABA transporters.
Increased Expression of VEGF and CD31 in Postradiation Rectal Tissue: Implications for Radiation Proctitis (2013)

Background. Inflammation mediators related to radiation proctitis are partially elucidated, and neovascularization is thought to play a key role. Objectives. To investigate the expression of vascular endothelial growth factor (VEGF) and CD31 as angiogenetic markers in postradiation rectal tissue. Methods. Rectal mucosa biopsies from 11 patients who underwent irradiation for prostate cancer were examined immunohistochemically for the expression of VEGF and CD31 at three time settings-before, at the completion of, and 6 months after radiotherapy. VEGF expressing vascular endothelial cells and CD31 expressing microvessels were counted separately in 10 high-power fields (HPFs). VEGF vascular index (VEGF-VI) and microvascular density (MVD) were calculated as the mean number of VEGF positive cells per vessel or the mean number of vessels per HPF, respectively. Histological features were also evaluated. Results. VEGF-VI was significantly higher at the completion of radiotherapy (0.17 ± 0.15 versus 0.41 ± 0.24, P = 0.001) declining 6 months after. MVD increased significantly only 6 months after radiotherapy (7.3 ± 3.2 versus 10.5 ± 3.1, P < 0.005). The histopathological examination revealed inflammatory changes at the completion of radiotherapy regressing in the majority of cases 6 months after. Conclusions. Our results showed that in postradiation rectal biopsy specimens neoangiogenesis seems to be inflammation-related and constitutes a significant postradiation component of the tissue injury.
Evidence that the p53 negative / Bcl-2 positive phenotype is an independent indicator of good prognosis in colorectal cancer: A tissue microarray study of 460 patients (2005)

Patient stratification by combined p53 / Bcl-2 phenotype provides stage-independent prognostic information in colorectal cancer. Specifically, that up to a quarter of patients display a good prognosis p53(-)/Bcl-2(+) phenotype. This may indicate a more clinically indolent phenotype and a subset of patients for whom less aggressive adjuvant treatment appropriate.