gebhart/patrepeval huggingface dataset:
Expanding Pd-Catalyzed C−N Bond-Forming Processes:  The First Amidation of Aryl Sulfonates, Aqueous Amination, and Complementarity with Cu-Catalyzed Reactions (2003)

The first general method for the Pd-catalyzed amination of aryl tosylates and benzenesulfonates was developed utilizing ligand 1, which belongs to a new generation of biaryl monophosphine ligands. In addition, the new catalyst system for the first time enables amidation of aryl arenesulfonates and aqueous amination protocols that do not necessitate the use of cosolvents. The substrate scope has been significantly expanded to include aryl halides containing primary amides and free carboxylic acid groups. In the case of multifunctional substrates, the Pd-catalyzed amination can provide selectivity that is complementary to the Cu-catalyzed C-N bond-forming processes.
Hypertrophic Cardiomyopathy (2003)

These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing MYBPC3 and MYH7 and then focus on TNNI3, TNNT2, and MYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.
Protective Effect of Endothelin Type A Receptor Antagonist on Brain Edema and Injury After Transient Middle Cerebral Artery Occlusion in Rats (2001)

Our data demonstrate that infusion with S-0139, an ET(A) antagonist, results in significant reduction of brain injury and plasma extravasation after transient MCAO. Thus, ETs may contribute to cerebral ischemia/reperfusion injury at least partly by increasing the BBB permeability via ET(A)s.
Tunable and Switchable Multiple-Cavity Thin Film Filters (2004)

A family of thin film interference filters is described that incorporates amorphous silicon layers for wide thermo-optic tunability and the potential for multiple cavity designs. Plasma enhanced chemical vapor deposition (PECVD) of hydrogenated amorphous silicon (a-Si:H) onto fused silica or crystalline silicon wafer substrates produces films with high index (n=3.71), low loss at 1500 nm (k<4/spl times/10/sup -6/), and thermo-optic index coefficients approximately ten times larger than those of the dielectric materials typically used in wavelength division multiplexing (WDM) filters. Pairing amorphous silicon with low index (n=1.77, k=1/spl times/10/sup -6/) silicon nitride companion layers followed by post-process annealing leads to multilayer film stacks which may be cycled up to 400 C without delamination or failure, resulting in thermal index modulations as large as 4% and enabling a wide variety of dynamic thin film device designs. In this paper we survey the range of device applications and show experimental demonstrations for two quite different classes of functionality. One class of filters is tunable in wavelength in the conventional sense. Single and dual-cavity narrowband filters are described with temperature coefficients of center wavelength 85-172 pm//spl deg/C in the 1550 nm WDM band and tuning ranges as large as 60 nm, an order of magnitude larger thermal tunability than for conventional thin film narrowband filters. A second class of filters is fixed in wavelength but switchable in transmission, based on hybrid structures which combine tunable semiconductor films and cavities with static dielectric films and cavities in an integrated coating design. To demonstrate the principle of a switchable add/drop filter, we fabricated a five-cavity, 117 layer, 200 GHz filter by combining a single cavity of a-Si:H/a-Si/sub x/N/sub y/ films deposited by PECVD with four cavities of dielectrics Ta/sub 2/O/sub 5//SiO/sub 2/ deposited by ion assisted e-beam evaporation. By varying the temperature, this device can be switched thermo-optically between transmission and reflection states at a fixed channel 1548.3 nm with a contrast ratio 18.4 dB. Stable devices can be obtained even with large internal temperature changes in microscopic volumes provided that layer-to-layer and layer-to-substrate adhesion is robust, film stresses are well controlled through coefficients of thermal expansion matching, and devices are annealed at or above maximum operational temperatures. "Hitless" filters can be obtained by structuring thermo-optic filters in two independently heated portions. Thermo-optically actuated thin film semiconductor devices are manufacturable and testable on a wafer scale and may be packaged by methods adapted from those for conventional thin film filters.
HUMAN ISLET TRANSPLANTATION (2000)

In islet autotransplantation, the reduced number of islets that can be isolated from fibrotic pancreata may be the major limiting factor. In islet allotransplantation, early graft function can now be consistently achieved. Islet allografts seem to be highly immunogenic, and chronic islet failure cannot be prevented consistently by conventional immunosuppression.
The Role of Moisture in Protein Stability (1988)

The importance of water sorption on solid state stability of proteins can be addressed through an understanding of properties of the sorbed water and its impact on the properties of the protein. Most decomposition reactions are minimal at or below the monolayer level of hydration. Sorption of water beyond that of the monolayer generally results in increased rates of decomposition due to the increased conformational flexibility of the protein and the ability of the less tightly bound water to mobilize reactants. In many cases the rates of decomposition can be influenced by the addition of excipients. An understanding of how such excipients can influence water sorption and stability will allow for improved development strategies to minimize the decomposition of proteins in the solid state.
Magnetic Resonance Imaging Detects Suppression of Tumor Vascular Permeability After Administration of Antibody to Vascular Endothelial Growth Factor (1998)

Macromolecular contrast medium-enhanced magnetic resonance imaging (MRI) and tumor-volume measurements were applied to monitor the effects of anti-vascular endothelial growth factor (anti-VEGF) antibody on microvascular characteristics and tumor growth of MDA-MB-435 human breast cancer cells implanted in nude rats. Administration of anti-VEGF antibody (three 1 mg doses at 3-day intervals) induced significant reductions in tumor growth rates (p < 0.05) and in MRI-assayed microvascular permeabilities (p < 0.05). Results of the study were consistent with previous observations that new microvessels formed in response to angiogenesis are hyperpermeable, and with the hypothesis that hyperpermeability is a mechanistic element in angiogenesis. Variations in tumor-vessel hyperpermeability can be measured by contrast-enhanced MRI, which may prove useful for assessing antiangiogenesis therapy.
Distinct responses of protein kinase C isozymes to c-erbB-2 activation in SKBR-3 human breast carcinoma cells. (1994)

We have studied the effect of activation of the c-erbB-2 receptor tyrosine kinase on protein kinase C (PKC) in cultured SKBR-3 human breast cancer cells. Treatment with the agonistic anti-receptor monoclonal antibody TAb 250 induces receptor autophosphorylation and stimulates phospholipase C-gamma 1 (L. K. Shawver et al. Cancer Res., 54: 1367-1373, 1994). TAb 250 induced a rapid and marked translocation of PKC histone phosphorylation activity to the particulate fraction of SKBR-3 cells. By immunoblot, however, this translocation was limited to specific PKC isozymes. beta PKC and zeta PKC translocated to the particulate fraction, whereas epsilon PKC underwent "partial reversed translocation" to the cell soluble fraction after receptor stimulation. Furthermore, beta PKC was rapidly degraded following TAb 250 treatment. By immunocytochemistry, beta IPKC translocated from the perinuclear area to the cytosol and into the nucleus, whereas zeta PKC translocated to the perinuclear region and into the nucleus. Consistent with the Western blot results, epsilon PKC translocated from the nucleus to the perinuclear area and the cytosol. These changes in the localization of PKC isozymes were not observed after addition of normal IgG1 or a nonagonistic anti-c-erbB-2 monoclonal antibody to SKBR-3 cells. alpha, beta II, or delta PKC present in these cells did not translocate following receptor stimulation. These data indicate that c-erbB-2 signal transduction may involve the activation of specific PKC isozymes. The biological role of these enzymes in the phenotype and cellular responses of c-erbB-2-overexpressing carcinoma cells remains to be studied.
Is the Combination of Sulfonylureas and Metformin Associated With an Increased Risk of Cardiovascular Disease or All-Cause Mortality? (2008)

The combination therapy of metformin and sulfonylurea significantly increased the RR of the composite end point of cardiovascular hospitalization or mortality (fatal and nonfatal events) irrespective of the reference group (diet therapy, metformin monotherapy, or sulfonylurea monotherapy); however, there were no significant effects of this combination therapy on either CVD mortality or all-cause mortality alone.
Electroretinographic analyses of Rpe65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. (2007)

We have taken the first steps toward developing an ERG assay of biologic activity of human grade vector for future clinical trials of RPE65-LCA. Faithful murine models of treatable human disease tested with specific ERG protocols may emerge as valuable in vivo bioassays for future human clinical trials of therapy in many retinal degenerative diseases.
Inactive conformation of an insulin despite its wild-type sequence (1997)

The peptide group between residues B24 and B25 of insulin was replaced by an ester bond. This modification only in the backbone was meant to eliminate a structurally important H-bond between the amide proton of B25 and the carbonyl oxygen of A19, and consequently to enhance detachment of the C-terminal B-chain from the body of the molecule, exposing the underlying A-chain. According to a model derived from the effects of side-chain substitutions, main-chain shortening, and crosslinking, this conformational change is prerequisite for receptor binding. Contrary to the expectation that increased flexibility would increase receptor binding and activity, depsi-insulin ([B24-B25 CO-O]insulin) has turned out be only 3-4% potent. In search of an explanation for this observation, the solution structure of depsi-insulin was determined by two-dimensional 1H-NMR spectroscopy. It was found that the loss of the B25-A19 H-bond does not entail detachment of the C-terminal B-chain. On the contrary, it is overcompensated by a gain in hydrophobic interaction achieved by insertion of the Phe B25 side chain into the molecule's core. This is possible because of increased rotational freedom in the backbone owing to the ester bond. Distortion of the B20-B23 turn and an altered direction of the distal B-chain are consequences that also affect self-association. The exceptional position of the B25 side chain is thus the key feature of the depsi-insulin structure. Being buried in the interior, it is not available for guiding the interaction with the receptor, a crucial role attributed to it by the model. This seems to be the main reason why the structure of depsi-insulin represents an inactive conformation.
Low-Temperature Sintering and Microwave Dielectric Properties of (1-x)MgTiO3–xCaTiO3Ceramics Using Bismuth Addition (2002)

The effects of bismuth addition on the microwave dielectric properties of (1-x)MgTiO3–xCaTiO3 ceramics were investigated. MgTiO3–CaTiO3 (hereafter referred to as MCT) ceramics was prepared by the conventional solid-state method. With a small amount of Bi2O3 addition, the sintering temperature of MCT ceramics can be effectively lowered without degrading the dielectric properties at microwave frequency. At a constant Mg/Ca ratio, the Q×f values are strongly dependent on the amount of Bi2O3 addition and decrease with increasing bismuth content owing to the decrease of density, while the εr value only shows a small increase. In the (1-x)MgTiO3–xCaTiO3 system, the microwave dielectric properties could be controlled by varying x. At 1250°C, 0.94MgTiO3–0.06CaTiO3 ceramics with 0.2 mol% Bi2O3 addition gives a dielectric constant εr of 22.6, a Q×f value of 53000 (7 GHz) and a τf value of -2.9 ppm/°C.
An animal model of cerebral infarction. Homologous blood clot emboli in rats. (1982)

An experimental model of cerebral infarction is created in rats by intracarotid injection of their homologous blood clots. This is the first small animal model in which embolization was achieved by homologous blood clots. The infarcts were produced predominantly in the territory of the middle cerebral artery. The low mortality rate and excellent reproduction rate make possible the correlative study of morphological, biochemical, and metabolic parameters at selected points in time to reconstruct the pathogenesis and natural history of focal cerebral ischemia and its relation to blood elements.
Pyrene Excimer‐Based Dual‐Emission Detection of a Oligoaspartate Tag‐Fused Protein by Using a ZnII–DpaTyr Probe (2007)

A dual-emission sensing system for proteins tethered to a repeated tetra-aspartate tag (D4-tag) was successfully developed by using the binding-induced excimer formation of the pyrene-appended ZnII–DpaTyr probe. This allows selective detection of the D4-tag-fused protein in a simple and convenient manner by the naked eye. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2268/2007/z700146_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Long‐term follow‐up of patients with NAFLD and elevated liver enzymes†‡ (2006)

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in patients of developed countries. We determined the long-term clinical and histological courses of such patients. In a cohort study, 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced (P = .01). These subjects more often died from cardiovascular (P = .04) and liver-related (P = .04) causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. The absence of periportal fibrosis at baseline had a negative predictive value of 100% in predicting liver-related complications. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg (P = .02), they were more insulin resistant (P = .04), and they exhibited more pronounced hepatic fatty infiltration (P = .03) at follow-up. In conclusion, NAFLD with elevated liver enzymes is associated with a clinically significant risk of developing end-stage liver disease. Survival is lower in patients with NASH. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.
Structural Mechanisms Determining Inhibition of the Collagen Receptor DDR1 by Selective and Multi-Targeted Type II Kinase Inhibitors (2014)

The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinases that are activated by the binding of triple-helical collagen. Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human diseases, including fibrosis, atherosclerosis and cancer. We report the inhibition of these unusual receptor tyrosine kinases by the multi-targeted cancer drugs imatinib and ponatinib, as well as the selective type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9nM. Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain that is stabilized by an unusual salt bridge between the activation loop and αD helix. Differences to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a β-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are therefore accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind potently to both the DDR and ABL kinases, the hydrophobic interactions of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 selectivity. Such inhibitors may have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer.
Sequestration of Heavy Metals from Water with Layered Metal Sulfides (2009)

Extraordinarily effective heavy metal ion scavenger: We show here that the material K(2x)Mn(x)Sn(3-x)S(6) (x = 0.5-0.95) (KMS-1) overcomes the limitations of the known heavy metal ion sorbents, showing the capability to rapidly reduce the concentrations of Cd, Hg, and Pb ions well-below the legally acceptable levels for drinking water. KMS-1 is inexpensive, easily prepared in large quantities, and may play a role in addressing the global problem of water contamination with heavy metal ions. The paradigm of heavy metal ion absorption of KMS-1 is the ability to form very strong M-S bonds.
Fast and reliable prediction of noncoding RNAs (2005)

We report an efficient method for detecting functional RNAs. The approach, which combines comparative sequence analysis and structure prediction, already has yielded excellent results for a small number of aligned sequences and is suitable for large-scale genomic screens. It consists of two basic components: (i) a measure for RNA secondary structure conservation based on computing a consensus secondary structure, and (ii) a measure for thermodynamic stability, which, in the spirit of a z score, is normalized with respect to both sequence length and base composition but can be calculated without sampling from shuffled sequences. Functional RNA secondary structures can be identified in multiple sequence alignments with high sensitivity and high specificity. We demonstrate that this approach is not only much more accurate than previous methods but also significantly faster. The method is implemented in the program rnaz, which can be downloaded from www.tbi.univie.ac.at/~wash/RNAz. We screened all alignments of length n > or = 50 in the Comparative Regulatory Genomics database, which compiles conserved noncoding elements in upstream regions of orthologous genes from human, mouse, rat, Fugu, and zebrafish. We recovered all of the known noncoding RNAs and cis-acting elements with high significance and found compelling evidence for many other conserved RNA secondary structures not described so far to our knowledge.
SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2 (2010)

SIRT proteins play an important role in the survival and drug resistance of tumor cells, especially during chemotherapy. In this study, we investigated the potency, specificity, and cellular targets of three SIRT inhibitors, Sirtinol, Salermide, and EX527. Cell proliferative and cell cycle analyses showed that Sirtinol and Salermide, but not EX527, were effective in inducing cell death at concentrations of 50 micromol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G(1) at comparable concentrations. In vitro SIRT assays using a p53 peptide substrate showed that all three compounds are potent SIRT1/2 inhibitors, with EX527 having the highest inhibitory activity for SIRT1. Computational docking analysis showed that Sirtinol and Salermide have high degrees of selectivity for SIRT1/2, whereas EX527 has high specificity for SIRT1 but not SIRT2. Consistently, Sirtinol and Salermide, but not EX527, treatment resulted in the in vivo acetylation of the SIRT1/2 target p53 and SIRT2 target tubulin in MCF-7 cells, suggesting that EX527 is ineffective in inhibiting SIRT2 and that p53 mediates the cytotoxic function of Sirtinol and Salermide. Studies using breast carcinoma cell lines and p53-deficient mouse fibroblasts confirmed that p53 is essential for the Sirtinol and Salermide-induced apoptosis. Further, we showed using small interfering RNA that silencing both SIRTs, but not SIRT1 and SIRT2 individually, can induce cell death in MCF-7 cells. Together, our results identify the specificity and cellular targets of these novel inhibitors and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death. Mol Cancer Ther; 9(4); 844-55. (c)2010 AACR.
Differential activation of virulence gene expression by PrfA, the Listeria monocytogenes virulence regulator (1995)

PrfA is a pleiotropic activator of virulence gene expression in the pathogenic bacterium Listeria monocytogenes. Several lines of evidence have suggested that a hierarchy of virulence gene activation by PrfA exists. This hypothesis was investigated by assessing the ability of PrfA to activate the expression of virulence gene fusions to lacZ in Bacillus subtilis. Expression of PrfA in this heterologous host was sufficient for activation of transcription at the hly, plcA, mpl, and actA promoters. Activation was most efficient at the divergently transcribed hly and plcA promoters. The putative PrfA binding site shared by these promoters is perfectly symmetrical and appears to represent the optimum sequence for target gene activation by PrfA. The activation of actA and mpl expression was considerably weaker and occurred more slowly than that observed at the hly and plcA promoters, suggesting that greater quantities of PrfA are required for productive interaction at these promoters. Interestingly, expression of an inlA-lacZ transcriptional fusion was very poorly activated by PrfA in B. subtilis, suggesting that other Listeria factors, in addition to PrfA, are required for PrfA-mediated activation at this promoter. Further support for the involvement of such factors was obtained by constructing and analyzing a prfA deletion mutant of L. monocytogenes. We observed that, in contrast to that of the other genes of the PrfA regulon, expression of inlA is only partially dependent on PrfA.