gebhart/patrepeval huggingface dataset:
Stapled Peptides Inhibitors: A New Window for Target Drug Discovery (2019)

Protein-protein interaction (PPI) is a hot topic in clinical research as protein networking has a major impact in human disease. Such PPIs are potential drugs targets, leading to the need to inhibit/block specific PPIs. While small molecule inhibitors have had some success and reached clinical trials, they have generally failed to address the flat and large nature of PPI surfaces. As a result, larger biologics were developed for PPI surfaces and they have successfully targeted PPIs located outside the cell. However, biologics have low bioavailability and cannot reach intracellular targets. A novel class -hydrocarbon-stapled α-helical peptides that are synthetic mini-proteins locked into their bioactive structure through site-specific introduction of a chemical linker- has shown promise. Stapled peptides show an ability to inhibit intracellular PPIs that previously have been intractable with traditional small molecule or biologics, suggesting that they offer a novel therapeutic modality. In this review, we highlight what stapling adds to natural-mimicking peptides, describe the revolution of synthetic chemistry techniques and how current drug discovery approaches have been adapted to stabilize active peptide conformations, including ring-closing metathesis (RCM), lactamisation, cycloadditions and reversible reactions. We provide an overview on the available stapled peptide high-resolution structures in the protein data bank, with four selected structures discussed in details due to remarkable interactions of their staple with the target surface. We believe that stapled peptides are promising drug candidates and open the doors for peptide therapeutics to reach currently "undruggable" space.
Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia (2009)

Certain malignant B cells rely on B-cell receptor (BCR)-mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.
Control of translational repression by protein - protein interactions (1992)

The coat protein of the RNA bacteriophage MS2 is a translational repressor and interacts with a specific RNA stem-loop to inhibit translation of the viral replicase gene. As part of an effort to dissect genetically its RNA binding function, mutations were identified in the coat protein sequence that suppress mutational defects in the translational operator. Each of the mutants displayed a super-repressor phenotype, repressing translation from the wild-type and a variety of mutant operators better than did the wild-type coat protein. At least one mutant probably binds RNA more tightly than wild-type. The other mutants, however, were defective for assembly of virus-like particles, and self-associated predominantly as dimers. It is proposed that this assembly defect accounts for their super-repressor characteristics, since failure to assemble into virus-like particles elevates the effective concentration of repressor dimers. This hypothesis is supported by the observation that deletion of thirteen amino acids known to be important for assembly of dimers into capsids also resulted in the same assembly defect and in super-repressor activity. A second class of assembly defects is also described. Deletion of two amino acids from the C-terminus of coat protein resulted in failure to form capsids, most of the coat protein having the apparent molecular weight expected of trimers. This mutant (dl-8) was completely defective for repressor activity, probably because of an inability to form dimers. These results point out the inter-dependence of the structural and regulatory functions of coat protein.
Bioactive molecules and the future of pulp therapy. (2003)

Direct capping of bioactive molecules or implantation of these molecules in the pulp may induce the formation of reparative dentin and coronal or radicular pulp mineralization. In this review, we summarize what is known and/or assumed on the biological mechanisms of these therapies. We report on the effects which were obtained experimentally in rat maxillary molars by implantation of Bone Sialoprotein (BSP)/collagen pellets and Specific Amelogenin Gene Splice Products [A+4] and [A-4]) adsorbed on agarose beads. The effects were compared with those of BMP-7 (OP-1) and Ca(OH)2. Depending on the molecule that was used, we obtained either the formation of a dentin bridge, or the filling of the pulp in the mesial part of the coronal pulp chamber, or the total mineralization of the root canal. These molecules may provide new therapeutic tools in the next future in dentistry.
Handbook of Detergents, Part D (2011)

Beyond use in the consumer markets, detergents affect applications ranging from automotive lubricants to remediation techniques for oil spills and other environmental contaminants, paper and textile processing, and the formulation of paints, inks, and colorants. Faced with many challenges and choices, formulators must choose the composition of dete
Epitope map and processing scheme for the 195,000-dalton surface glycoprotein of Plasmodium falciparum merozoites deduced from cloned overlapping segments of the gene. (1986)

DNA fragments from human malaria parasites were cloned into lambda gt11 to produce a genomic DNA expression library. A pool of monoclonal antibodies (mAbs) recognizing three domains of the 195-kDa major merozoite surface glycoprotein (gp195) reacted with seven clones expressing malaria antigens. mAbs recognizing the 83-kDa product of gp195 reacted with the clones, but mAbs recognizing a glycosylated 45-kDa and a nonglycosylated 45-kDa domain did not. Restriction enzyme mapping revealed that the clones contained overlapping segments encoding about 70% of the gene beginning at the 5' end and ending at an EcoRI restriction enzyme site 3.3 kilobase pairs downstream. The mAbs recognizing the 83-kDa domain reacted differently with the clones, allowing the mapping of three epitopes, one of which was repetitive. Affinity-purified antibodies were selected from immune monkey serum with recombinant expression proteins adsorbed to nitrocellulose filters. When used to probe electrophoretic immunoblots of parasite extracts, these antigen-selected antibodies reacted with specific sets of processed products of gp195, including those associated with the 83- and the nonglycosylated 45-kDa domains. This information, combined with the mAb epitope map, allowed a tentative scheme for processing gp195 from the Camp strain to be proposed.
NIEMANN PICK DISEASE: PRESENCE OF THE MAGNESIUM‐DEPENDENT SPHINGOMYELINASE IN BRAIN OF THE INFANTILE FORM OF THE DISEASE1 (1978)

Abstract— Brain of a 14‐month‐old patient with the infantile form of Niemann Pick disease was found to be practically devoid of sphingomyelinase activity when assayed at pH 5. When assayed at pH 7.4, in the presence of magnesium ions considerable hydrolysis of sphingomyelin was obtained by brain preparations. The rate of hydrolis of a homogenate of grey matter was about 0.3 μmol. mg protein −1 . H −1 , corresponding to about 15 μmol of sphingomyelin hydrolysed perg brain in 1 h. The possibility is suggested that the presence of the extra‐lysosomal, magnesium dependent sphingomyelinase in brain of Niemann Pick patients may be responsible, in part, for the lesser accumulation of sphingomyelin in this tissue relative to other organs, such as liver or spleen.
High-speed parallel Viterbi decoding: algorithm and VLSI-architecture (1991)

The Viterbi algorithm (VA) is considered as an example of a fairly complex algorithm that needs to be implemented for high-speed applications. A brief introduction to the algorithm is given, and the state of the art of high-speed Viterbi decoders is reviewed. The three principal levels of introducing additional parallelism into an algorithm-bit level, word level, and algorithm level-are outlined, and a solution for the VA at the bit level is indicated.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
TRPV4 Forms a Novel Ca 2+ Signaling Complex With Ryanodine Receptors and BK Ca Channels (2005)

Vasodilatory factors produced by the endothelium are critical for the maintenance of normal blood pressure and flow. We hypothesized that endothelial signals are transduced to underlying vascular smooth muscle by vanilloid transient receptor potential (TRPV) channels. TRPV4 message was detected in RNA from cerebral artery smooth muscle cells. In patch-clamp experiments using freshly isolated cerebral myocytes, outwardly rectifying whole-cell currents with properties consistent with those of expressed TRPV4 channels were evoked by the TRPV4 agonist 4alpha-phorbol 12,13-didecanoate (4alpha-PDD) (5 micromol/L) and the endothelium-derived arachidonic acid metabolite 11,12 epoxyeicosatrienoic acid (11,12 EET) (300 nmol/L). Using high-speed laser-scanning confocal microscopy, we found that 11,12 EET increased the frequency of unitary Ca2+ release events (Ca2+ sparks) via ryanodine receptors located on the sarcoplasmic reticulum of cerebral artery smooth muscle cells. EET-induced Ca2+ sparks activated nearby sarcolemmal large-conductance Ca2+-activated K+ (BKCa) channels, measured as an increase in the frequency of transient K+ currents (referred to as "spontaneous transient outward currents" [STOCs]). 11,12 EET-induced increases in Ca2+ spark and STOC frequency were inhibited by lowering external Ca2+ from 2 mmol/L to 10 micromol/L but not by voltage-dependent Ca2+ channel inhibitors, suggesting that these responses require extracellular Ca2+ influx via channels other than voltage-dependent Ca2+ channels. Antisense-mediated suppression of TRPV4 expression in intact cerebral arteries prevented 11,12 EET-induced smooth muscle hyperpolarization and vasodilation. Thus, we conclude that TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels that elicits smooth muscle hyperpolarization and arterial dilation via Ca2+-induced Ca2+ release in response to an endothelial-derived factor.
Estimating and adapting to registration errors in augmented reality systems (2003)

All augmented reality (AR) systems must deal with registration errors. While most AR systems attempt to minimize registration errors through careful calibration, registration errors can never be completely eliminated in any realistic system. In this paper, we describe a robust and efficient statistical method for estimating registration errors. Our method generates probabilistic error estimates for points in the world, in either 3D world coordinates or 2D screen coordinates. We present a number of examples illustrating how registration error estimates can be used in AR interfaces, and describe a method for estimating registration errors of objects based on the expansion and contraction of their 2D convex hulls.
Systemic signalling of adverse reactions to drugs. (1974)

Many national centres now cooperate with the World Health Organization in a system for monitoring information on suspected adverse reactions to therapeutic drugs. Proposals are made here for various methods of systematically producing signals from the computer files, with the object of indicating disproportions in frequencies that may be due to adverse reactions. Signals are intended to arouse suspicions and to stimulate deeper investigation; they are not to be equated with warnings of danger. Emphasis is laid on the dissemination of signals to national centres and on the logic of interpretation. Particularly important is restriction of the number of non-urgent signals, so as to ensure a reasonable chance of thorough investigation nationally for each that is transmitted.
Mapping image processing algorithms onto abstract multiprocessors (1994)

The need for parallel computing technology is rapidly growing in several image processing applications, such as industrial quality control, bio-medical imaging, traffic control automation. Most of the image processing algorithms are inherently computationally intensive and may require vast computing power if strict time-constraints are posed. The spreading of parallel image processing techniques and systems has been driven not only by the afore-mentioned need, but the inherent parallel nature of many image processing algorithms has also eased this evolution. The execution characteristics of a certain parallel algorithm on a given architecture heavily depends on the 'mutual conformance' of the mentioned algorithm and the architecture pair. Two algorithms with similar sequential performance may behave very differently in a parallel environment. In sequential algorithms the complexity is expressed in terms of operations and storage. In parallel environments these terms are not adequate for characterizing the computing efficiency - fewer operations does not directly mean shorter execution time since there is a definite overhead involved due to availability of resources and communication between processors.
Reducing the Burden of Diabetes: The National Diabetes Education Program (1998)

The National Diabetes Education Program (NDEP) is a joint initiative sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health and the Division of Diabetes Translation of the Centers for Disease Control and Prevention. The program will develop a partnership of public and private organizations and implement educational activities to help reduce the morbidity and mortality associated with diabetes and its complications. Participating public and private organizations include the Indian Health Service, the Department of Veterans Affairs, the American Diabetes Association, the American College of Physicians, the American Dietetic Association, and the American Association of Diabetes Educators. Key program activities will include (1) ongoing public awareness and education (2) and identification and dissemination of existing educational tools and resources for patients and their families, health care providers, and payers and purchasers of health care. The NDEP will also sponsor the development and dissemination of new educational tools and resources, including science-based guidelines, efforts to improve quality and access to diabetes care, and program evaluation.
Miniature cylindrical ion traps and arrays (2001)

A quadrupole ion trap mass analyzer with simplified geometry, the cylindrical ion trap (CIT), was shown to be well-suited to use in miniature mass spectrometers and even mass spectrometer arrays. Experiments with a single miniature CIT showed acceptable resolution and sensitivity, limited by the ion trapping capacity of the miniature device. Parallel miniature CIT arrays, with each CIT of the same size, were operated with the same rf and ac voltages applied to all of the CITs in the array. In this mode of operation, the array was shown to increase ion trapping capacity and thus sensitivity, compared to a single miniature CIT. Parallel miniature CIT arrays with each CIT of a different size were also examined. In this type of array, each CIT was operated to trap a single mass-to-charge ratio without the need to ramp the rf voltage. A multiple-ion monitoring experiment can be performed in the array, and the rf voltage necessary for operation is simplified and greatly reduced in amplitude. Because of the reduced rf voltage, this type of array is suitable for a fully miniaturized mass spectrometer system that operates under size and power restrictions. Further improvements were also made to improve the resolution of miniature CITs by use of nonlinear resonance ejection, which also facilitated operation with air, instead of helium, as the buffer gas. Non-destructive image current detection in a full sized CIT was also performed. In addition, an improved method of image current detection, differential detection was demonstrated in a hyperbolic ion trap. This new method gives increased signal intensity as well as reduced noise.
The Housing Industry and Union Power: An Economic Analysis (1973)

In October, 1972, there was every expectation that the issue of the anticompetitive influence of construction trades unions on the low- and moderate-income housing industry would be hotly debated over the next few years. Two recent actions by President Nixon have mooted the issue for the present.
Aberrantly plumaged barbets (1983)

(Uploaded by Plazi from the Biodiversity Heritage Library) No abstract provided.
Control of cardiac Ca2+ levels. Inhibitory actions of sphingosine on Ca2+ transients and L-type Ca2+ channel conductance. (1994)

The naturally occurring second messenger sphingosine (SPH) was examined for its ability to influence cardiac myocyte Ca2+ regulation. SPH inhibited intracellular Ca2+ transients in adult and neonatal rat ventricular myocytes. The inhibition was steeply dose dependent, with complete blockage of the Ca2+ transients occurring in the 20- to 25-mumol/L range. Whole-cell patch clamping revealed substantial inhibition of the L-type Ca2+ channel current (ICa) by SPH. The ability of SPH to block both the Ca2+ transients and ICa was not dependent on protein kinases, since the general protein kinase inhibitor H7 failed to prevent the actions of SPH. The specificity of the effect of SPH was determined in experiments showing that SPH analogues did not produce comparable effects. Neither the naturally occurring ceramide, N-stearoyl SPH, nor the cell-permeant ceramide, N-acetyl SPH, had SPH-like actions on the Ca2+ transients or L-type channel conductances. Caffeine-induced Ca2+ transients were also inhibited by the actions of SPH on cardiac sarcoplamic reticulum Ca2+ release, and the threshold for caffeine-induced Ca2+ release was raised. We conclude that SPH inhibits excitation-contraction coupling in cardiac myocytes by reducing the amount of entering "trigger Ca2+" for Ca(2+)-induced Ca2+ release and by simultaneously raising the threshold of the ryanodine receptor for Ca(2+)-induced Ca2+ release. Consequently, we propose that sphingolipids produced by the sphingomyelin signal transduction pathway could be physiologically relevant regulators of cardiac [Ca2+]i and therefore cardiac contractility.
Buffy-Coat-Derived PlateletConcentrates Prepared fromHalf-Strength Citrate CPD andCPD Whole-Blood Units (1995)

The in vitro effects of storage of platelets prepared from 4 or 6 pooled buffy coat (BC) units and stored in a platelet storage medium consisting of 30-40% of CPD plasma or alternatively halfstrength citrate CPD (0.5 CPD) plasma and 60-70% of different alternative platelet additive solutions (PASs) were evaluated. Measurements of mean platelet volume, pH, pCT, pC02, bicarbonate, glucose, lactate, ATP, total adenine nucleotide content, extracellular lactate dehydrogenase or adenylate kinase activity, as markers for disintegration of platelets, and extracellular ß-thromboglobulin, as a marker for activation of platelets, were included in the in vitro studies. Previous studies indicated that a reduction of the citrate concentration from the standard 21 to 8 mmol/1 is associated with a significant reduction of the consumption of glucose and production of lactate. Alternatively, similar effects can be obtained by the addition of acetate. In a preliminary paired study, the effects of different concentrations of acetate were tested. In an additional paired study, the effects of CPD plasma in combination with either saline or a PAS containing NaCl (115.5 mmol/1), citrate (10 mmol/1), and acetate (30 mmol/1), pH 7.2 (PAS-2) were evaluated. 0.5CPD plasma in combination with either PAS-2 or a nonacetate PAS (PAS-1) were also tested. The storage of platelets in 0.5CPD plasma was used as a reference. The conclusions are: (1) A minimum acetate concentration of 30 mmol/1 is needed to counteract the effects of citrate on the production of lactate. (2) pH and the bicarbonate buffering capacity are significantly better maintained in PAS-2 than in PAS-I. With PAS-2, a significantly lower consumption of glucose and a significantly lower production of lactate are also observed. (3) When the storage period exceeds 5 days, PAS-2 is superior to saline as plasma diluent with regard to the maintenance of pH. (4) A significantly lower consumption of glucose was noted in 0.5CPD plasma diluted with PAS-2 as compared to undiluted 0.5CPD plasma. A significantly better maintenance ofbicarbonate buffering capacity was also seen. (5) By comparing PAS-2 in combination with either CPD or 0.5CPD, significantly lower values for pC02 and consumption of glucose were observed with 0.5CPD. The levels of pH and p02 are significantly higher with 0.5CPD. We conclude that PAS-2 during 9-day storage is associated with the most stable storage conditions with regard to the in vitro variables used in this study. The results suggest that at least 7 days storage of PCs in a medium consisting of 30% of either standard CPD or 0.5CPD plasma and 70% PAS-2 is possible.
Src kinase-mediated signaling in leukocytes (2000)

A concert of antigens, antibodies, cytokines, adhesion molecules, lipid factors, and their different receptors mediate leukocyte development and inflammatory responses. Regardless of the stimulus and receptor type, members of the Src family of protein tyrosine kinases (PTKs) play a critical role in initiating the numerous intracellular signaling pathways. Recruited and activated by the receptor, these Src PTKs amplify and diversify the signal. Multiple pathways arise, which affect cell migration, adhesion, phagocytosis, cell cycle, and cell survival. Essential nonredundant properties of Src PTKs have been identified through the use of gene targeting in mice or in the somatic cell line DT40. Because of their role in mediating leukocyte proliferation and activation, Src PTKs serve as excellent drug targets. Inhibitors of Src family members and dependent pathways may be useful in the treatment of human diseases similar to drugs known to inhibit other signal transduction pathways.