gebhart/patrepeval huggingface dataset:
Design and evaluation of nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence. (1999)

We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA. In human tissues, the specific phosphodiesterase type 5 inhibitor zaprinast potentiated the relaxing effects of the nitrosylated compounds. Only nitrosylated compounds induced accumulation of cyclic GMP in rabbit corpus cavernosum strips. Yohimbine and NMI-187 demonstrated a potent alpha2-blocking activity, with no significant differences in pA2 values (8.9 versus 8.2, respectively). Moxisylyte and NMI-221 showed moderate potency in antagonizing phenylephrine contraction, with comparable pA2 values for both molecules (6.5 versus 6.6, respectively). alpha-Adrenergic receptor-binding studies showed similar binding affinities for the alpha-ARA and their corresponding nitrosylated compounds. In vivo, intracavernosal injection of nitrosylated molecules caused greater increases in intracavernosal pressure (NMI-221 versus moxisylyte) that were more long lasting than those of moxisylyte or yohimbine. There were no significant differences between nitrosylated and non-nitrosylated compounds in the magnitude of systemic mean arterial pressure decrease after intracavernosal injection. alpha-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated alpha-ARA have the dual functionalities of nitric oxide donors and alpha-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.
Endoplasmic reticulum stress compromises the ubiquitin–proteasome system (2005)

The presence of endoplasmic reticulum (ER) stress and impaired ubiquitin-proteasome system (UPS) activity has been independently implicated in the pathophysiology of conformational diseases. Here, we reveal a link between ER stress and the functionality of the UPS. Treatment of cells with different ER stressors delayed the degradation of an ER reporter substrate and caused a subtle but consistent accumulation of three independent nuclear/cytosolic UPS reporter substrates. A similar signature increase was observed upon induction of ER stress in transgenic mice expressing a reporter substrate. Cells undergoing ER stress failed to clear efficiently UBB+1, an aberrant ubiquitin found in conformational diseases, which in turn caused general impairment of the UPS. We conclude that ER stress has a general inhibitory effect on the UPS. The compromised UPS during ER stress may explain the long-term gradual accumulation of misfolded proteins as well as the selective vulnerability of particular cell populations in conformational diseases.
Routing tree construction under fixed buffer locations (2000)

Modern high performance design requires using a large number of buffers. In practice, buffers are organized into buffer blocks and planned in the early stages of design process [1]. Thus, the locations of buffer blocks are usually fixed prior to routing tree construction. In this paper we present the first algorithm for simultaneous routing tree construction and buffer insertion for multiple-pin nets under fixed buffer locations. Given a source and n sinks of a net, the required arrival time associated with each sink, and m buffers with fixed locations, our algorithm can construct a routing tree for this net with possible insertion of buffers at given locations such that the required arrival time at the source is maximized. Experimental results show that our algorithm is efficient to handle fixed buffer location constraints and can also be used for routing tree construction without buffer insertion. Moreover, it can handle obstacles and congestion which will benefit its adaption in a global router. Compared to the well-known BA-tree algorithm [2] followed by a post-processing step for handling fixed buffer location constraints, our algorithm outperforms it by up to 46% in terms of delay while using comparative wirelength.
Glycosylation and Secretion of Human Tissue Plasminogen Activator in Recombinant Baculovirus-Infected Insect Cells (1989)

Cell lines established from the lepidopteran insect Spodoptera frugiperda (fall armyworm; Sf9) are used routinely as hosts for the expression of foreign proteins by recombinant baculovirus vectors. We have examined the pathway of protein glycosylation and secretion in these cells, using human tissue plasminogen activator (t-PA) as a model. t-PA expressed in Sf9 cells was both N glycosylated and secreted. At least a subset of the N-linked oligosaccharides in extracellular t-PA was resistant to endo-beta-N-acetyl-D-glucosaminidase H, which removes immature, high-mannose-type oligosaccharides. This refutes the general conclusion from previous studies that Sf9 cells cannot process immature N-linked oligosaccharides to an endo-beta-N-acetyl-D-glucosaminidase H-resistant form. A nonglycosylated t-PA precursor was not detected in Sf9 cells, even with very short pulse-labeling times. This suggests that the mammalian signal sequence of t-PA is efficiently recognized in Sf9 cells and that it can mediate rapid translocation across the membrane of the rough endoplasmic reticulum, where cotranslational N glycosylation takes place. However, t-PA was secreted rather slowly, with a half-time of about 1.6 h. Thus, a rate-limiting step(s) in secretion occurs subsequent to translocation and N glycosylation of the t-PA polypeptide. Treatment of Sf9 cells with tunicamycin, but not with inhibitors of oligosaccharide processing, prevented the appearance of t-PA in the extracellular medium. This suggests that N glycosylation per se, but not processing of the N-linked oligosaccharides, is required directly or indirectly in baculovirus-infected Sf9 cells for the secretion of t-PA. Finally, the relative efficiency of secretion decreased dramatically with time of infection, suggesting that the Sf9 host cell secretory pathway is compromised during the later stages of baculovirus infection.
Design of $LCL$ Filters of Active-Front-End Two-Level Voltage-Source Converters (2009)

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> This paper introduces a new iterative design procedure of <formula formulatype="inline"><tex Notation="TeX">$L$</tex> </formula> and <formula formulatype="inline"><tex Notation="TeX">$LCL$</tex></formula> filters for low-voltage active-front-end PWM two-level voltage source converters. The analytical expression of the converter harmonic voltages by Bessel functions is applied to design the filter parameters for defined maximum grid current harmonics. Different filter designs are derived for various resonance frequencies and inductance split factors of <formula formulatype="inline"> <tex Notation="TeX">$LCL$</tex></formula> filter. The minimum amount of stored energy of passive components is used to select a final filter design. A voltage-oriented control scheme, including active damping, is applied in the (400 V and 50 kVA) experimental setup. Both simulation and experimental investigations are presented to verify the accuracy of the filter design procedure. Finally, the steady state and transient performance of the active front end with different <formula formulatype="inline"><tex Notation="TeX">$LCL$</tex></formula> filters are depicted. </para>
Discrimination of Transgenic Maize Kernel Using NIR Hyperspectral Imaging and Multivariate Data Analysis (2017)

There are possible environmental risks related to gene flow from genetically engineered organisms. It is important to find accurate, fast, and inexpensive methods to detect and monitor the presence of genetically modified (GM) organisms in crops and derived crop products. In the present study, GM maize kernels containing both <i>cry1Ab/cry2Aj-G10evo</i> proteins and their non-GM parents were examined by using hyperspectral imaging in the near-infrared (NIR) range (874.41-1733.91 nm) combined with chemometric data analysis. The hypercubes data were analyzed by applying principal component analysis (PCA) for exploratory purposes, and support vector machine (SVM) and partial least squares discriminant analysis (PLS-DA) to build the discriminant models to class the GM maize kernels from their contrast. The results indicate that clear differences between GM and non-GM maize kernels can be easily visualized with a nondestructive determination method developed in this study, and excellent classification could be achieved, with calculation and prediction accuracy of almost 100%. This study also demonstrates that SVM and PLS-DA models can obtain good performance with 54 wavelengths, selected by the competitive adaptive reweighted sampling method (CARS), making the classification processing for online application more rapid. Finally, GM maize kernels were visually identified on the prediction maps by predicting the features of each pixel on individual hyperspectral images. It was concluded that hyperspectral imaging together with chemometric data analysis is a promising technique to identify GM maize kernels, since it overcomes some disadvantages of the traditional analytical methods, such as complex and monotonous sampling.
Direct Measurement of AMPA Receptor Desensitization Induced by Glutamatergic Synaptic Transmission (1996)

Although almost all ionotropic neurotransmitter receptors undergo desensitization, the onset and recovery of desensitization at a synapse have never been observed directly. We have found changes in postsynaptic AMPA receptor sensitivity in neurons of the chick cochlear nucleus, the nucleus magnocellularis (nMAG), by photolysis of caged glutamate immediately after activation of a single synaptic input. Additionally, synaptic desensitization was demonstrated via competition between synaptically released glutamate and an exogenous nondesensitizing agonist, kainate. Both approaches indicated that at least 35-40% of the receptors were desensitized after a single synaptic stimulus. Miniature synaptic currents were depressed after an evoked synaptic current, indicating that desensitization led to a reduction in the response to individual transmitter quanta. Stimulation of adjacent glutamatergic inputs to the same cell demonstrated that nearby terminals did not depress one another, suggesting that the desensitizing level of glutamate is restricted to each axon terminal. These findings confirm that postsynaptic neurons may use desensitization to regulate the strength of transmission on a synapse-specific basis.
Methylation Defect in Imprinted Genes Detected in Patients with an Albright's Hereditary Osteodystrophy Like Phenotype and Platelet Gs Hypofunction (2012)

In conclusion, this is the first report of methylation defects including GNAS in patients with an AHO-like phenotype without endocrinological abnormalities. Additional studies are still needed to correlate the methylation defect with the clinical phenotype.
The use of animal models in the study of diabetes mellitus. (2009)

Animal models have enormously contributed to the study of diabetes mellitus, a metabolic disease with abnormal glucose homeostasis, due to some defect in the secretion or the action of insulin. They give researchers the opportunity to control in vivo the genetic and environmental factors that may influence the development of the disease and establishment of its complications, and thus gain new information about its handling and treatment in humans. Most experiments are carried out on rodents, even though other species with human-like biological characteristics are also used. Animal models develop diabetes either spontaneously or by using chemical, surgical, genetic or other techniques, and depict many clinical features or related phenotypes of the disease. In this review, an overview of the most commonly used animal models of diabetes are provided, highlighting the advantages and limitations of each model, and discussing their usefulness and contribution in the field of diabetes research.
Estimation of left ventricular cavity area with an on-line, semiautomated echocardiographic edge detection system. (1992)

Real-time on-line automated edge detection provides accurate estimation of manually drawn cavity areas. Although the method is gain dependent, measurements are reproducible. The system should have clinical application in settings in which measurements of left ventricular function are important.
MIT Autonomous Vehicle Technology Study: Large-Scale Deep Learning Based Analysis of Driver Behavior and Interaction with Automation (2017)

Today, and possibly for a long time to come, the full driving task is too complex an activity to be fully formalized as a sensing-acting robotics system that can be explicitly solved through model-based and learning-based approaches in order to achieve full unconstrained vehicle autonomy. Localization, mapping, scene perception, vehicle control, trajectory optimization, and higher-level planning decisions associated with autonomous vehicle development remain full of open challenges. This is especially true for unconstrained, real-world operation where the margin of allowable error is extremely small and the number of edge-cases is extremely large. Until these problems are solved, human beings will remain an integral part of the driving task, monitoring the AI system as it performs anywhere from just over 0% to just under 100% of the driving. The governing objectives of the MIT Autonomous Vehicle Technology (MIT-AVT) study are to (1) undertake large-scale real-world driving data collection, and (2) gain a holistic understanding of how human beings interact with vehicle automation technology. In pursuing these objectives, we have instrumented 21 Tesla Model S and Model X vehicles, 2 Volvo S90 vehicles, and 2 Range Rover Evoque vehicles for both long-term (over a year per driver) and medium term (one month per driver) naturalistic driving data collection. The recorded data streams include IMU, GPS, CAN messages, and high-definition video streams of the driver face, the driver cabin, the forward roadway, and the instrument cluster. The study is on-going and growing. To date, we have 78 participants, 7,146 days of participation, 275,589 miles, and 3.5 billion video frames. This paper presents the design of the study, the data collection hardware, the processing of the data, and the computer vision algorithms currently being used to extract actionable knowledge from the data.
Accelerated lifetime tests on UV written intra-coregratings in boron germaniacodoped silica fibre (1995)

Accelerated life tests carried out over 10000 h at temperatures below 200°C suggest that UV written gratings in hot hydrogenated boron germania codoped silica fibres can be made to have vanishingly small changes in the reflectivity when held for 80°C over 25 years if they first receive an appropriate burn-in.
Rhodium-Catalyzed Reductive Cyclization of 1,6-Diynes and 1,6-Enynes Mediated by Hydrogen:  Catalytic C−C Bond Formation via Capture of Hydrogenation Intermediates (2004)

Catalytic hydrogenation of carbon-, nitrogen- and oxygen-tethered 1,6-diynes 1a-9a and 1,6-enynes 10a-18a using cationic Rh(I) precatalysts at ambient temperature and pressure enables reductive carbocyclization to afford 1,2-dialkylidene cyclopentanes 1b-9b and monoalkylidene cyclopentanes 10b-18b, respectively, in good to excellent yields and as single alkene stereoisomers. Notably, the 1,3-diene and alkene containing cyclization products 1b-9b and 10b-18b are not subject to over-reduction under the conditions of catalytic hydrogenation in which they are formed. Reductive cyclization 1,6-diyne 1a and 1,6-enyne 10a performed under an atmosphere of D(2) provides the carbocyclization products deuterio-1b and deuterio-10b, respectively, which incorporate two deuterium atoms. The collective data are consistent with a catalytic mechanism involving heterolytic activation of elemental hydrogen (H(2) + Rh(+)X(-) --> Rh-H + HX) followed by Rh(I)-mediated oxidative cyclization of the 1,6-diyne or 1,6-enyne substrates to afford (hydrido)Rh(III)-based metallocyclopentadiene and metallocyclopentene intermediates, respectively. These transformations represent the first examples of metal-catalyzed reductive carbocyclization mediated by hydrogen.
Stereoisomerism and Biological Activity of the Selective and Superactive αvβ3Integrin Inhibitor cyclo(-RGDfV-) and Its Retro-Inverso Peptide (1997)

The cyclic pentapeptide cyclo(-Arg-Gly-Asp-d-Phe-Val-) is a highly potent and selective inhibitor for the αvβ3 integrin and is a prospective anticancer drug by acting to inhibit angiogenesis and by inducing apoptosis in vascular cells. The cyclic retro-inverso peptides as well as the inverso and the cyclic retro peptide analogs of the four cyclic Arg-Gly-Asp-Phe-Val peptides with one amino acid in the d configuration and the corresponding all-l peptide have been synthesized. The inhibitory activities of 18 compounds have been tested on the isolated integrin αIIbβ3 and αvβ3 receptors. The conformations of the cyclic retro-inverso pentapeptides were investigated by NMR spectroscopy using NOEs, ROEs, and coupling constants and were determined by distance geometry (DG) calculations. The structures were compared to their parent analogs, and the relationship between their conformation and the biological activity is discussed. Due to the reversal of the peptide bonds in the retro-inverso peptides, the hydrogen bond pattern is shifted and the spatial structure differs from its parent compound structure. These conformational changes result in a dramatic decrease of activity in comparison to the high-active parent peptides. On the other hand the retro-inverso peptide analog of the poorly active parent peptide cyclo(-d-Arg-Gly-Asp-Phe-Val-) was found to be highly active and selective for the αvβ3 receptor. Furthermore, the almost perfect similarity of the side chain orientation between the highly active peptide cyclo(-Arg-Gly-Asp-d-Phe-Val-) and the inactive retro-inverso peptide cyclo(-Val-d-Phe-d-Asp-Gly-d-Arg-) indicates a distinct interaction of at least one peptide bond of the backbone with the αvβ3 receptor.
Clustering method using self-organizing map (2002)

As a step towards developing a high-performance image retrieval system, we propose a clustering method that efficiently classifies image objects having an unknown probability distribution, without requiring the determination of complicated parameters, through the use of a self-organizing map (SOM) and a method of image processing. To ensure that this clustering method is fast and highly reliable, we defined a hierarchical SOM and used it to construct the clustering method. Experiments using artificial image data confirmed the basic performance and adaptability of the SOM for clustering images. We also confirmed experimentally and theoretically that our clustering method using the hierarchical SOM is faster than one using a non-hierarchical SOM for the objects used in these experiments.
Targeted degradation of mRNA inXenopusoocytes and embryos directed by modified oligonucleotides: studies of An2 and cyclin in embryogenesis (1990)

We have designed antisense oligodeoxyribonucleotides which are both highly resistant to nucleolytic degradation and also serve as substrates for ribonuclease H. Using these compounds we have targeted the specific degradation of several maternal mRNAs present in Xenopus laevis oocytes and early embryos. Several internucleoside linkages at both the 3' and 5' ends of the oligonucleotides were modified as phosphoramidates to provide complete protection against exonucleases, the predominant nucleolytic activity found in both oocytes and embryos. Eight Internal linkages were left unmodified to provide a substrate for RNase H. Degradation of specific embryonic mRNAs was accomplished using subtoxic amounts of the modified oligonucleotides. Specific depletion of An2, a localized mRNA encoding the alpha subunit of the mitochondrial ATPase, produced embryos that gastrulated later than control embryos and arrested in development prior to neurulation. A modified oligonucleotide targeting Xenopus cyclin B1 and cyclin B2 mRNA was also synthesized. Following the injection of one blastomere of a two-cell embryo with the anti-cyclin oligonucleotide, cell division in that half of the embryo was inhibited, demonstrating the in vivo importance of these cyclins in mitosis. The oligonucleotide analogs described here should be useful in studying developmentally significant proteins in Xenopus.
α‐MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV‐induced DNA damage in human melanocytes (2009)

One skin cancer prevention strategy that we are developing is based on synthesizing and testing melanocortin analogs that reduce and repair DNA damage resulting from exposure to solar ultraviolet (UV) radiation, in addition to stimulating pigmentation. Previously, we reported the effects of tetrapeptide analogs of alpha-melanocortin (alpha-MSH) that were more potent and stable than the physiological alpha-MSH, and mimicked its photoprotective effects against UV-induced DNA damage in human melanocytes. Here, we report on a panel of tripeptide analogs consisting of a modified alpha-MSH core His(6)-d-Phe(7)-Arg(8), which contained different N-capping groups, C-terminal modifications, or arginine mimics. The most potent tripeptides in activating cAMP formation and tyrosinase of human melanocytes were three analogs with C-terminal modifications. The most effective C-terminal tripeptide mimicked alpha-MSH in reducing hydrogen peroxide generation and enhancing nucleotide excision repair following UV irradiation. The effects of these three analogs required functional MC1R, as they were absent in human melanocytes that expressed non-functional receptor. These results demonstrate activation of the MC1R by tripeptide melanocortin analogs. Designing small analogs for topical delivery should prove practical and efficacious for skin cancer prevention.
Extended release anti-VEGF systems: a strategy whose time has come? Or already gone? (2016)

KEYWORDS: Age-related macular degenerationanti-VEGFdegenerationvision lossdiabetic macular edemaanti-VEGF drugs
Antisense inhibition of gene expression in cells by oligonucleotides incorporating locked nucleic acids: effect of mRNA target sequence and chimera design (2002)

Use of antisense oligonucleotides is a versatile strategy for achieving control of gene expression. Unfortunately, the interpretation of antisense-induced phenotypes is sometimes difficult, and chemical modifications that improve the potency and specificity of antisense action would be useful. The introduction of locked nucleic acid (LNA) bases into oligonucleotides confers exceptional improvement in binding affinity, up to 10 degrees C per substitution, making LNAs an exciting option for the optimization of antisense efficacy. Here we examine the rules governing antisense gene inhibition within cells by oligonucleotides that contain LNA bases. LNA- containing oligomers were transfected into cells using cationic lipid and accumulated in the nucleus. We tested antisense gene inhibition by LNAs and LNA-DNA chimeras complementary to the 5'-untranslated region, the region surrounding the start codon and the coding region of mRNA, and identified effective antisense agents targeted to each of these locations. Our data suggest that LNA bases can be used to develop antisense oligonucleotides and that their use is a versatile approach for efficiently inhibiting gene expression inside cells.