gebhart/patrepeval huggingface dataset:
Specificity of Memapsin 1 and Its Implications on the Design of Memapsin 2 (β-Secretase) Inhibitor Selectivity (2002)

Memapsin 1 is closely homologous to memapsin 2 (BACE), or beta-secretase, whose action on beta-amyloid precursor protein (APP) leads to the production of beta-amyloid (A beta) peptide and the progression of Alzheimer's disease. Memapsin 2 is a current target for the development of inhibitor drugs to treat Alzheimer's disease. Although memapsin 1 hydrolyzes the beta-secretase site of APP, it is not significantly present in the brain, and no direct evidence links it to Alzheimer's disease. We report here the residue specificity of eight memapsin 1 subsites. In substrate positions P(4), P(3), P(2), P(1), P(1)', P(2)', P(3)', and P(4)', the most preferred residues are Glu, Leu, Asn, Phe, Met, Ile, Phe, and Trp, respectively, while the second preferred residues are Gln, Ile, Asp, Leu, Leu, Val, Trp, and Phe, respectively. Other less preferred residues can also be accommodated in these subsites of memapsin 1. Despite the broad specificity, these residue preferences are strikingly similar to those of human memapsin 2 [Turner et al. (2001) Biochemistry 40, 10001-10006] and thus pose a serious problem to the design of differentially selective inhibitors capable of inhibiting memapsin 2. This difficulty was confirmed by the finding that several potent memapsin 2 inhibitors effectively inhibited memapsin 1 as well. Several possible approaches to overcome this problem are discussed.
A general technique for non-blocking trees (2014)

We describe a general technique for obtaining provably correct, non-blocking implementations of a large class of tree data structures where pointers are directed from parents to children. Updates are permitted to modify any contiguous portion of the tree atomically. Our non-blocking algorithms make use of the LLX, SCX and VLX primitives, which are multi-word generalizations of the standard LL, SC and VL primitives and have been implemented from single-word CAS. To illustrate our technique, we describe how it can be used in a fairly straightforward way to obtain a non-blocking implementation of a chromatic tree, which is a relaxed variant of a red-black tree. The height of the tree at any time is O(c + log n), where n is the number of keys and c is the number of updates in progress. We provide an experimental performance analysis which demonstrates that our Java implementation of a chromatic tree rivals, and often significantly outperforms, other leading concurrent dictionaries.
Analysis of Small GTPase Signaling Pathways Using p21-activated Kinase Mutants That Selectively Couple to Cdc42 (2001)

p21-activated kinase 1 (Pak1) is an effector for the small GTPases Cdc42 and Rac. Because Pak1 binds to and is activated by both these GTPases, it has been difficult to precisely delineate the signaling pathways that link extracellular stimuli to Pak1 activation. To separate activation of Pak1 by Cdc42 versus activation by Rac, we devised a genetic screen in yeast that enabled us to create and identify Pak1 mutants that selectively couple to Cdc42 but not Rac1. We recovered several such Pak1 mutants and found that the residues most often affected lie within the p21 binding domain, a region previously known to mediate Pak1 binding to GTPases, but that several mutations also map outside the borders of the p21 binding domain. Pak1 mutants that associate with Cdc42 but not Rac1 were also activated by Cdc42 but not Rac1. In rat 3Y1 cells expressing oncogenic Ha-Ras, the Pak1 mutants defective in Rac1 binding are not activated, suggesting that Ras signals through a GTPase other than Cdc42 to activate Pakl. Similar results were obtained when epidermal growth factor was used to activate Pak1. However, Pak1 mutants that are unable to bind Rac are nonetheless well activated by calf serum, implying that this stimulus may induce Pak activation independent of Rac.
Imaging laser heated subsurface chromophores in biological materials: determination of lateral physical dimensions (1996)

We describe a non-contact method using infrared radiometry to determine lateral physical dimensions of laser heated subsurface chromophores in biological materials. An imaging equation is derived that relates measured radiometric temperature change to the reduced two-dimensional temperature increase of laser heated chromophores. From measured images of radiometric temperature change, the lateral physical dimensions of chromophores positioned in an in vitro model of human skin are determined by deconvolution of the derived imaging equation using a non-negative constrained conjugate gradient algorithm. Conditions for optimum spatial resolution are found by analysis of a derived radiometric transfer function and correspond to superficial chromophores and/or weak infrared absorption in a laser irradiated biological material. Analysis indicates that if the infrared attenuation coefficient is sufficiently small (i.e., less than 10mm-1), infrared radiometry in combination with a deconvolution algorithm allows estimation of lateral physical dimensions of laser heated subsurface chromophores in human skin.
Inflammatory bowel disease (2009)

Inflammatory bowel diseases (IBDs) are associated with platelet activation and an increased risk for thromboembolism. While the mechanisms that underlie the altered platelet function and hypercoagulable state in IBD remain poorly understood, emerging evidence indicates that inflammation and coagulation are interdependent processes that can initiate a vicious cycle wherein each process propagates and intensifies the other. This review addresses the mechanisms that may account for the mutual activation of coagulation and inflammation during inflammation and summarizes evidence that implicates a role for platelets and the coagulation system in the pathogenesis of human and experimental IBD. The proposed link between inflammation and coagulation raises the possibility of targeting the inflammation-coagulation interface to reduce the morbidity and mortality associated with IBD.
Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency (2020)

Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV's plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position <i>i</i> caused termination of RNA synthesis at position <i>i</i>+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2'-C-methylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral.
Comparision of frequency and time domain differential modulation in an OFDM system for wireless ATM (2003)

Wireless ATM systems at 5.2 GHz will use OFDM as the transmission scheme to combat the frequency selective radio channel. Differential modulation, e.g. DQPSK, is proposed in combination with OFDM to provides a cost-effective solution without the need for equalization. Depending on whether the differential modulated symbols are placed on the same sub-carrier of adjacent OFDM symbols or on different sub-carriers of the same OFDM symbol time domain and frequency domain modulation can be distinguished. Based on new closed-form BER expressions for OFDM/DQPSK transmission schemes with frequency and time domain differential modulation the performance with regard to the radio channel characteristic and the protocols for wireless ATM at 5.2 GHz are investigated.
Inverse halftoning and kernel estimation for error diffusion (1995)

Two different approaches in the inverse halftoning of error-diffused images are considered. The first approach uses linear filtering and statistical smoothing that reconstructs a gray-scale image from a given error-diffused image. The second approach can be viewed as a projection operation, where one assumes the error diffusion kernel is known, and finds a gray-scale image that will be halftoned into the same binary image. Two projection algorithms, viz., minimum mean square error (MMSE) projection and maximum a posteriori probability (MAP) projection, that differ on the way an inverse quantization step is performed, are developed. Among the filtering and the two projection algorithms, MAP projection provides the best performance for inverse halftoning. Using techniques from adaptive signal processing, we suggest a method for estimating the error diffusion kernel from the given halftone. This means that the projection algorithms can be applied in the inverse halftoning of any error-diffused image without requiring any a priori information on the error diffusion kernel. It is shown that the kernel estimation algorithm combined with MAP projection provide the same performance in inverse halftoning compared to the case where the error diffusion kernel is known.
Activation of mislocalized opsin kills rod cells: A novel mechanism for rod cell death in retinal disease (2002)

Rod photoreceptors are highly compartmentalized sensory neurons that maintain strict ultrastructural and molecular polarity. Structural subdivisions include the outer segment, inner segment, cell body, and synaptic terminal. The visual pigment rhodopsin is found predominantly in membranes of the rod cell outer segment but becomes mislocalized, appearing throughout the plasma membrane of the cell in many retinal diseases and injuries. Currently, there is no known link between rhodopsin redistribution and rod cell death. We propose that activation of mislocalized rhodopsin kills rod cells by stimulating normally inaccessible signaling pathways. This hypothesis was tested in primary retinal cell cultures, which contain photoreceptors. In rod photoreceptors, opsin immunofluorescence occurred throughout the rod cell plasma membrane. Activation of this mislocalized opsin by photostimulation after formation of isorhodopsin or by incubation with beta-ionone (opsin agonist) killed 19-30% of rod cells. Rod cell death was apoptotic, as indicated by marked chromatin condensation and the requirement for caspase-3 activation. Rod cell death could be induced by forskolin (adenylate cyclase agonist), and conversely, beta-ionone-induced cell death could be blocked by cotreatment with SQ22536 (an adenylate cyclase inhibitor). Pertussis toxin (a G protein inhibitor) also blocked beta-ionone-induced cell death. The data support a mechanism by which activation of mislocalized opsin initiates apoptotic rod cell death through G protein stimulation of adenylate cyclase.
PASADENA Hyperpolarization of Succinic Acid for MRI and NMR Spectroscopy (2008)

We use the PASADENA (parahydrogen and synthesis allow dramatically enhanced nuclear alignment) method to achieve 13C polarization of approximately 20% in seconds in 1-13C-succinic-d2 acid. The high-field 13C multiplets are observed as a function of pH, and the line broadening of C1 is pronounced in the region of the pK values. The 2JCH, 3JCH, and 3JHH couplings needed for spin order transfer vary with pH and are best resolved at low pH leading to our use of pH approximately 3 for both the molecular addition of parahydrogen to 1-13C-fumaric acid-d2 and the subsequent transfer of spin order from the nascent protons to C1 of the succinic acid product. The methods described here may generalize to hyperpolarization of other carboxylic acids. The C1 spin-lattice relaxation time at neutral pH and 4.7 T is measured as 27 s in H2O and 56 s in D2O. Together with known rates of succinate uptake in kidneys, this allows an estimate of the prospects for the molecular spectroscopy of metabolism.
Nucleolin Is a Protein Kinase C-ζ Substrate (1997)

We have previously shown that protein kinase C (PKC)-zeta is activated and required for nerve growth factor (NGF)-induced differentiation of rat pheochromocytoma PC12 cells (Wooten, M. W., Zhou, G., Seibenhener, M. L., and Coleman, E. S. (1994) Cell Growth & Diff. 5, 395-403; Coleman, E. S., and Wooten, M. W. (1994) J. Mol. Neurosci. 5, 39-57). Here we report the characterization and identification of a 106-kDa nuclear protein as a specific substrate of PKC-zeta. NGF treatment of PC12 cells resulted in translocation of PKC-zeta and coincident phosphorylation of a protein that was localized within the nucleoplasm of nuclei isolated from PC12 cells. Addition of PKC-zeta pseudosubstrate peptide in vitro or myristoylated peptide in vivo diminished phosphorylation of pp106 in a dose-dependent fashion. Likewise, addition of purified PKC-zeta, but neither PKC-alpha nor delta, to nuclear extracts resulted in an incremental increase in the phosphorylation of pp106. Expression of dominant-negative PKC-zeta inhibited NGF-induced phosphorylation of pp106, by comparison overexpression of PKC-zeta enhanced basal phosphorylation without a noticeable effect upon NGF-induced effects. Amino acid sequence analysis of four peptides derived from purified pp106 revealed that this protein was homologous to nucleolin. Using an in vitro reconstitution system, purified nucleolin was likewise shown to be phosphorylated by purified PKC-zeta. The staining intensity of both enzyme and substrate in the nucleus increased upon treatment with NGF. In vivo labeling with 32Pi and stimulation of PC12 cells with NGF followed by immunoprecipitation with anti-nucleolin antibody corroborated the in vitro approach documenting enhanced phosphorylation of nucleolin by NGF treatment. Taken together, the findings presented herein document that nucleolin is a target of PKC-zeta that serves to relay NGF signals from cell surface to nucleus in PC12 cells.
Plasma derivatives and viral hepatitis (1982)

Plasma derivatives can be separated into those with either a low or a high risk of transmitting viral hepatitis. Low-risk products, with few exceptions, will remain low-risk irrespective of the plasma from which they are manufactured because they are heated at 60 degrees C for 10 hours (Albumin, Plasma Protein Fraction) or because they contain protective antibodies (Immune Globulin). This would appear to be the case not only for hepatitis B but also for non-A, non-B hepatitis. The risk of hepatitis B associated with plasma derivatives is reduced but not eliminated by HBsAg screening of donors. Further decreasing the risk of hepatitis B associated with AHF or Factor IX lots, as well as newer products like AT-III, alpha-1 antitrypsin, Fibronectin, C-1 Inactivator, and Factor XIII, may be accomplished either by the combination of stabilization and heating or by assuring that these products contain an excess of anti-HBS. For highly-purified products with little residual immunoglobulin it may be necessary to add anti-HBs. The addition of antibodies against non-A, non-B hepatitis agents when they are identified, could prevent transmission of both forms of viral hepatitis by plasma derivatives. Methods to stabilize and heat high-risk plasma derivatives to inactivate hepatitis viruses have the potential to remove both hepatitis B and non-A, non-B hepatitis infectivity.
Essential Role of DAP12 Signaling in Macrophage Programming into a Fusion-Competent State (2008)

Multinucleated giant cells, formed by fusion of macrophages, are a hallmark of granulomatous inflammation. With a genetic approach, we show that signaling through the adaptor protein DAP12 (DNAX activating protein of 12 kD), its associated receptor triggering receptor expressed by myeloid cells 2 (TREM-2), and the downstream protein tyrosine kinase Syk is required for the cytokine-induced formation of giant cells and that overexpression of DAP12 potentiates macrophage fusion. We also present evidence that DAP12 is a general macrophage fusion regulator and is involved in modulating the expression of several macrophage-associated genes, including those encoding known mediators of macrophage fusion, such as DC-STAMP and Cadherin 1. Thus, DAP12 is involved in programming of macrophages through the regulation of gene and protein expression to induce a fusion-competent state.
CVXPY: A Python-Embedded Modeling Language for Convex Optimization. (2016)

CVXPY is a domain-specific language for convex optimization embedded in Python. It allows the user to express convex optimization problems in a natural syntax that follows the math, rather than in the restrictive standard form required by solvers. CVXPY makes it easy to combine convex optimization with high-level features of Python such as parallelism and object-oriented design. CVXPY is available at http://www.cvxpy.org/ under the GPL license, along with documentation and examples.
IN VITRO MUTAGENESIS (1985)

TOTAL SYNTHESIS OF MUTANTS . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 Solid Phase Chemical Synthesis of Oligodeoxyribonucleotides .. . ..... 424 Assembly of Oligodeoxyribonucleotides into Double-Strand DNA 427 Mutation by Partial Gene Synthesis (Cassette Mutagenesis) 428 OLIGODEOXYRIBONUCLEOTIDE HETERODUPLEX MUTAGENESIS . . . . . . . . . . . . . . . 428 Oligonucleotide Mutagenesis Using Single-Strand Vectors 431 Oligonucleotide Mutagenesis Using Double-Strand Vectors ........ 433 Plasmids with a Filamentous Phage Origin of Replication 435 Selection and Enrichment of Mutants 435 Screening for Mutants 437 TARGETED RANDOM POINT MUTATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438 Chemical Reagents that Change Base Pairing Specificity 439 Chemical Reagents that Eliminate Base Pairing. . . . ..... . 440 Enzymatic Incorporation of Nucleotide Analogs that Induce Mispairing ... 441 Enzymatic Misincorporation of Nucleotides.. 441 Random Point Mutations Using Long Synthetic Oligonucleotides with a Low Level of Misincorporuted Nucleotides ..... .... . ..... 443 Screening and Selection for Mutations Produced by Random Point Mutagenesis..... 444 DELETION AND INSERTION MUTAGENESIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 Deletion Mutagenesis .... .... . . 444 Linker Insertion Mutagenesis . . . . 445 IN VITRO CONSTRUCTIONS THAT TARGET IN VIVO MUTAGENESIS . . .. . . . . . . . . 446 ALLELE REPLACEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446 CHARACTERIZATION OF MUTANTS 447 In Situ Characterization of Mutants .. .... . .. . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . . ...... . . . . . . .... . . 447 Recovery of Genetic Functions Prior to Characterization 448 Reversion by Site-Specific Mutagenesis 448
Rates of spontaneous mutation among RNA viruses. (1993)

Simple methods are presented to estimate rates of spontaneous mutation from mutant frequencies and population parameters in RNA viruses. Published mutant frequencies yield a wide range of mutation rates per genome per replication, mainly because mutational targets have usually been small and, thus, poor samples of the mutability of the average base. Nevertheless, there is a clear central tendency for lytic RNA viruses (bacteriophage Q beta, poliomyelitis, vesicular stomatitis, and influenza A) to display rates of spontaneous mutation of approximately 1 per genome per replication. This rate is some 300-fold higher than previously reported for DNA-based microbes. Lytic RNA viruses thus mutate at a rate close to the maximum value compatible with viability. Retroviruses (spleen necrosis, murine leukemia, Rous sarcoma), however, mutate at an average rate about an order of magnitude lower than lytic RNA viruses.
Measurement of 5–Hydroxyindole Compounds During L-5–HTP Treatment in Depressed Patients (1976)

L-5-hydroxytryptophan (L-5-HTP), an immediate serotonin precursor, was given to the hospitalized depressed patients in an open clinical trial of the Phase 2 study for antidepressive effects of the agent. A relatively small dose, 150mg orally for seven days, was employed, and seven of 14 patients responded to the treatment with mild or moderate emelioration of their depressive symptoms. Urinary excretion levels and plasma concentrations of three 5-hydroxyindole compounds, 5-HTP, 5-HT and 5-HIAA, were measured during the drug treatment. Approximately 70% of the orally administered dose of L-5-HTP was recovered from the urine of depressed patients. Major part of urinary indoleamine metabolites was free and conjugate 5-HIAA. Excretion levels of these compounds in urine were not consistenly altered in the depressed patients as compared to those in normal subjects. Clinical response to L-5-HTP treatment appeared to have some correlation with the biochemical measures in the depressed patients, that is, non-responders exhibited significantly lower excretion levels of 5-HT and 5-HIAA in urine, and lower plasma levels of 5-HT than responders. Administered L-5-HTP may not be fully utilized in the depressed patients who did not react to the agent.
Nucleotide sequence of a mutant eukaryotic gene: the yeast tyrosine-inserting ochre suppressor SUP4-o. (1977)

One of the eight endonuclease EcoRI fragments of yeast DNA that hybridize to yeast tRNATyr has been identified with the genetically defined nonsense-suppressor locus SUP4. This identification was achieved by analyzing the meiotic linkage between the genetic determinant for the SUP4 phenotype and that for an electrophoretic variant of the EcoRI fragment. The SUP4 gene was then cloned from an ochre-suppressing yeast strain and analyzed by DNA sequencing. A wild-type SUP4 gene and two other genetically unidentified tRNATyr genes were also sequenced. The sequence of the ochre suppressor differs from that of the wild-type genes by virtue of a G.C leads to T.A transversion in the base pair that codes for the wobble position base of the tRNATyr anticodon. All four genes contain, immediately to the 3' side of the anticodon triplet, a 14 base pair tract that is not present in mature tRNATyr. Although the four genes, which represent three unlinked chromosomal loci, all encode the same mature tRNA sequence, there is virtually no observable sequence homology between the three loci in the region preceding the 5' end of the mature tRNATyr sequences.