gebhart/patrepeval huggingface dataset:
Structure-Based Virtual Screening of MT2 Melatonin Receptor: Influence of Template Choice and Structural Refinement (2013)

Developing GPCR homology models for structure-based virtual screening requires the choice of a suitable template and refinement of binding site residues. We explored this systematically for the MT2 melatonin receptor, with the aim to build a receptor homology model that is optimized for the enrichment of active melatoninergic ligands. A set of 12 MT2 melatonin receptor models was built using different GPCR X-ray structural templates and submitted to a virtual screening campaign on a set of compounds composed of 29 known melatonin receptor ligands and 2560 drug-like decoys. To evaluate the effect of including a priori information in receptor models, 12 representative melatonin receptor ligands were placed into the MT2 receptor models in poses consistent with known mutagenesis data and with assessed pharmacophore models. The receptor structures were then adapted to the ligands by induced-fit docking. Most of the 144 ligand-adapted MT2 receptor models showed significant improvements in screening enrichments compared to the unrefined homology models, with some template/refinement combinations giving excellent enrichment factors. The discriminating ability of the models was further tested on the 29 active ligands plus a set of 21 inactive or low-affinity compounds from the same chemical classes. Rotameric states of side chains for some residues, presumed to be involved in the binding process, were correlated with screening effectiveness, suggesting the existence of specific receptor conformations able to recognize active compounds. The top MT2 receptor model was able to identify 24 of 29 active ligands among the first 2% of the screened database. This work provides insights into the use of refined GPCR homology models for virtual screening.
Signal peptidases recognize a structural feature at the cleavage site of secretory proteins. (1988)

The cloning of the gene for staphylococcal nuclease A in the pIN-III-OmpA secretion vector results in a hybrid protein which is processed by signal peptidase I, yielding an active form of the nuclease that is secreted across the cytoplasmic membrane (Takahara, M., Hibler, D., Barr, P. J., Gerlt, J. A., and Inouye, M. (1985) J. Biol. Chem. 260, 2670-2674). Using oligonucleotide-directed site-specific mutagenesis, we have constructed a set of mutants at the cleavage site area of the precursor hybrid protein designed to alter progressively the predicted secondary structure of the cleavage site. Our results show that processing becomes increasingly defective as the turn probability decreases. These results are consistent with the structural requirement that we found for the processing of lipoprotein by signal peptidase II (Inouye, S., Duffaud, G., and Inouye, M. (1986) J. Biol. Chem. 261, 10970-10975). We conclude that secretory precursor proteins have a distinct secondary structural requirement at their cleavage site for processing by signal peptidase I, as well as by signal peptidase II.
An efficient memory system for the SIMD construction of a Gaussian pyramid (1996)

In this paper, a memory system is introduced for the efficient construction of a Gaussian pyramid. The memory system consists of an address calculating circuit, an address routing circuit, a memory module selection circuit, and 2/sup n/+1 memory modules. The memory system provides parallel access to 2/sup n/ image points whose patterns are a block, a row or a column, where the interval of the column and the block is 1 and the interval of the row is 2/sup l/,l/spl ges/0. The performance of a generic SIMD (single-instruction multiple-data) processor using the proposed memory system is compared with one using an interleaved memory system for the construction of a Gaussian pyramid. The ratio of the time of the construction of level 2 and level 10 from the original image (level 0) of an SIMD processor with an interleaved memory system to that of the proposed memory system is 1.485 and 1.633, respectively.
Synthekines are surrogate cytokine and growth factor agonists that compel signaling through non-natural receptor dimers (2017)

Cytokine and growth-factor ligands typically signal through homo- or hetero-dimeric cell surface receptors via Janus Kinase (JAK/TYK), or Receptor Tyrosine Kinase (RTK)-mediated trans-phosphorylation. However, the number of receptor dimer pairings occurring in nature is limited to those driven by natural ligands encoded within our genome. We have engineered synthethic cytokines (synthekines) that drive formation of cytokine receptor dimer pairings that are not formed by endogenous cytokines and that are not found in nature, and which activate distinct signaling programs. We show that a wide range of non-natural cytokine receptor hetero-dimers are competent to elicit a signaling output. We engineered synthekine ligands that assembled IL-2Rβ/IL-4Rα or IL-4Rα/IFNAR2 receptor heterodimers, that do not occur naturally, triggering signaling and functional responses distinct from those activated by the endogenous cytokines IL-2, IL-4, and IFN. Furthermore, hybrid synthekine ligands that dimerized a JAK/STAT cytokine receptor with a receptor tyrosine kinase (RTK) also elicited a signaling response. Synthekines represent a new family of synthetic ligands with pre-defined receptors, but 'orphan' functions, that enable the full combinatorial scope of dimeric signaling receptors encoded within the human genome to be exploited for basic research and drug discovery.
The function of SULTR2;1 sulfate transporter during seed development in Arabidopsis thaliana (2005)

SULTR2;1 is a low‐affinity sulfate transporter expressed in the vascular tissues of roots and leaves for interorgan transport of sulfate in Arabidopsis thaliana . Transgenic Arabidopsis carrying a fusion gene construct of SULTR2;1 5′‐promoter region and β‐glucuronidase coding sequence (GUS) demonstrated that within the reproductive tissues, SULTR2;1 is specifically expressed in the bases and veins of siliques and in the funiculus, which connects the seeds and the silique. The antisense suppression of SULTR2;1 mRNA caused decrease of sulfate contents in seeds and of thiol contents both in seeds and leaves, as compared with the wildtype (WT). The effect of antisense suppression of SULTR2;1 on seed sulfur status was determined by introducing a sulfur‐indicator construct, p35S::β SR x3:GUS, which drives the expression of GUS reporter under a chimeric cauliflower mosaic virus 35S promoter containing a triplicate repeat of sulfur‐responsive promoter region of soybean β‐conglycinin β subunit (β SR x3). The mature seeds of F1 plants carrying both the SULTR2;1 antisense and p35S::β SR x3:GUS constructs exhibited significant accumulation of GUS activities on sulfur deficiency, as compared with those carrying only the p35S::β SR x3:GUS construct in the WT background. These results suggested that SULTR2;1 is involved in controlling translocation of sulfate into developing siliques and may modulate the sulfur status of seeds in A. thaliana .
Design of an Active Ultrastable Single-chain Insulin Analog (2008)

Single-chain insulin (SCI) analogs provide insight into the inter-relation of hormone structure, function, and dynamics. Although compatible with wild-type structure, short connecting segments (<3 residues) prevent induced fit upon receptor binding and so are essentially without biological activity. Substantial but incomplete activity can be regained with increasing linker length. Here, we describe the design, structure, and function of a single-chain insulin analog (SCI-57) containing a 6-residue linker (GGGPRR). Native receptor-binding affinity (130 +/- 8% relative to the wild type) is achieved as hindrance by the linker is offset by favorable substitutions in the insulin moiety. The thermodynamic stability of SCI-57 is markedly increased (DeltaDeltaG(u) = 0.7 +/- 0.1 kcal/mol relative to the corresponding two-chain analog and 1.9 +/- 0.1 kcal/mol relative to wild-type insulin). Analysis of inter-residue nuclear Overhauser effects demonstrates that a native-like fold is maintained in solution. Surprisingly, the glycine-rich connecting segment folds against the insulin moiety: its central Pro contacts Val(A3) at the edge of the hydrophobic core, whereas the final Arg extends the A1-A8 alpha-helix. Comparison between SCI-57 and its parent two-chain analog reveals striking enhancement of multiple native-like nuclear Overhauser effects within the tethered protein. These contacts are consistent with wild-type crystal structures but are ordinarily attenuated in NMR spectra of two-chain analogs, presumably due to conformational fluctuations. Linker-specific damping of fluctuations provides evidence for the intrinsic flexibility of an insulin monomer. In addition to their biophysical interest, ultrastable SCIs may enhance the safety and efficacy of insulin replacement therapy in the developing world.
Smallest stable human chromosomes created (1996)

RETURN TO ISSUEPREVNewsNEXTSmallest stable human chromosomes createdSTU BORMANCite this: Chem. Eng. News 1996, 74, 30, 42Publication Date (Print):July 22, 1996Publication History Published online12 November 2010Published inissue 22 July 1996https://pubs.acs.org/doi/10.1021/cen-v074n030.p042https://doi.org/10.1021/cen-v074n030.p042newsACS PublicationsCopyright © 1996 AMERICAN CHEMICAL SOCIETYArticle Views5Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access options SUBJECTS:Biochemistry,Cell physiology,Elements,Fungi,Genetics Get e-Alerts
Phylogenetic comparisons suggest that distance from the locus control region guides developmental expression of primate β-type globin genes (2006)

Phylogenetic inferences drawn from comparative data on mammalian beta-globin gene clusters indicate that the ancestral primate cluster contained a locus control region (LCR) and five paralogously related beta-type globin loci (5'-LCR-epsilon-gamma-psieta-delta-beta-3'), with epsilon and gamma expressed solely during embryonic life. A gamma locus tandem duplication (5'-gamma(1)-gamma(2)-3') triggered gamma's evolution toward fetal expression but by a different trajectory in platyrrhines (New World monkeys) than in catarrhines (Old World monkeys and apes, including humans). In platyrrhine (e.g., Cebus) fetuses, gamma(1) at the ancestral distance from epsilon is down-regulated, whereas gamma(2) at increased distance is up-regulated. Catarrhine gamma(1) and gamma(2) acquired longer distances from epsilon (14 and 19 kb, respectively), and both are up-regulated throughout fetal life with gamma(1)'s expression predominating over gamma(2)'s. On enlarging the platyrrhine expression data, we find Aotus gamma is embryonic, Alouatta gamma is inactive at term, and in Callithrix, gamma(1) is down-regulated fetally, whereas gamma(2) is up-regulated. Of eight mammalian taxa now represented per taxon by embryonic, fetal, and postnatal beta-type globin gene expression data, four taxa are primates, and data for three of these primates are from this laboratory. Our results support a model in which a short distance (<10 kb) between epsilon and the adjacent gamma is a plesiomorphic character that allows the LCR to drive embryonic expression of both genes, whereas a longer distance (>10 kb) impedes embryonic activation of the downstream gene.
Validating the Diagnosis of Sensory Processing Disorders Using EEG Technology (2007)

These results present empirical evidence that children with SPD display unique brain processing mechanisms compared to children who are typically developing and provide external validity for the diagnosis of SPD.
Far and near visual acuity with multifocal intraocular lenses in an optomechanical eye model with imaging capability (2007)

Multifocal IOLs of different optical designs were well characterized and distinguished by simulated contrast acuity testing in an experimental eye model, allowing quantitative comparison. Their overall visual performance, averaged over contrast and distance, was not superior to the performance of a monofocal IOL without an additional correcting lens.
Effect of low intravenous doses of TRH, acid‐TRH and cyclo(His‐Pro) on cerebral and peripheral blood flows (1986)

Local cerebral and peripheral blood flow in conscious and anaesthetized rabbits were investigated with the microsphere method, before and after the i.v. administration of 25 or 50 micrograms kg-1 thyrotropin-releasing hormone (TRH). Before the experiment, the cervical sympathetic chain was sectioned on one side in order to evaluate the possible effect of the sympathetic nerves on cranial and extracranial blood flows. Blood flow was also determined in anaesthetized rabbits before and after the administration of the TRH metabolites cyclo(His-Pro) and acid-TRH and after subsequent administration of 50 micrograms kg-1 TRH. TRH caused an increase in mean arterial blood pressure (MAP) of about 1 to 2 kPa whereas cyclo(His-Pro) and acid-TRH had no effect on MAP. In the anaesthetized animal an increase in total cerebral blood flow (CBFtot), from 71 +/- 7 to 107 +/- 12 g min-1 100 g-1 (P less than 0.05) was observed on the sympathetic intact side after 25 micrograms kg-1 TRH and a further increase to 130 +/- 9 g min-1 100g-1 (P less than 0.01) after 50 micrograms kg-1 TRH. A similar effect was observed on the sympathotomized side. An effect on CBF in the conscious animal was not detected. The control CBFtot (104 +/- 8 g min-1 100g-1) was higher in these animals than in the anaesthetized animals (P less than 0.02). Neither cyclo(His-Pro) nor acid-TRH mimicked the effect of TRH on CBF. In several peripheral tissues, e.g. skin, pancreas and gastric mucosa, a reduction in blood flow was noted after the administration of TRH in both anaesthetized and conscious rabbits. It was concluded that TRH can induce cerebral vasodilatation in animals with a depressed CBF, whereas the vasoconstrictor effect of TRH in peripheral organs is not markedly affected by the state of consciousness.
Force measurements in E-cadherin–mediated cell doublets reveal rapid adhesion strengthened by actin cytoskeleton remodeling through Rac and Cdc42 (2004)

We have used a modified, dual pipette assay to quantify the strength of cadherin-dependent cell-cell adhesion. The force required to separate E-cadherin-expressing paired cells in suspension was measured as an index of intercellular adhesion. Separation force depended on the homophilic interaction of functional cadherins at the cell surface, increasing with the duration of contact and with cadherin levels. Severing the link between cadherin and the actin cytoskeleton or disrupting actin polymerization did not affect initiation of cadherin-mediated adhesion, but prevented it from developing and becoming stronger over time. Rac and Cdc42, the Rho-like small GTPases, were activated when E-cadherin-expressing cells formed aggregates in suspension. Overproduction of the dominant negative form of Rac or Cdc42 permitted initial E-cadherin-based adhesion but affected its later development; the dominant active forms prevented cell adhesion outright. Our findings highlight the crucial roles played by Rac, Cdc42, and actin cytoskeleton dynamics in the development and regulation of strong cell adhesion, defined in terms of mechanical forces.
Possibility of the expression of a cloned human erythropoietin gene in CHO cells (1989)

The human a r antitrypsin gene has been cloned. A cDNA molecule, containing almost the whole coding sequence is isolated. Nucleotide sequence is determined for the regulatory region of ct]AT gene, responsible for its expression in the liver. The possibility to use cloned genes for the gene therapy of some diseases is discussed.
Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection (1998)

Potent combinations of antiretroviral drugs diminish the turnover of CD4+ T lymphocytes productively infected with HIV-1 and reduce the large pool of virions deposited in lymphoid tissue (LT). To determine to what extent suppression of viral replication and reduction in viral antigens in LT might lead correspondingly to repopulation of the immune system, we characterized CD4+ T lymphocyte populations in LT in which we previously had quantitated viral load and turnover of infected cells before and after treatment. We directly measured by quantitative image analysis changes in total CD4+ T cell counts, the CD45RA+ subset, and fractions of proliferating or apoptotic CD4+ T cells. Compared with normal controls, we documented decreased numbers of CD4+ T cells and increased proliferation and apoptosis. After treatment, proliferation returned to normal levels, and total CD4+ T and CD45RA+ cells increased. We discuss the effects of HIV-1 on this subset based on the concept that renewal mechanisms in the adult are operating at full capacity before infection and cannot meet the additional demand imposed by the loss of productively infected cells. The slow increases in the CD45RA+ CD4+ T cells are consistent with the optimistic conclusions that (i) renewal mechanisms have not been damaged irreparably even at relatively advanced stages of infection and (ii) CD4+ T cell populations can be partially restored by control of active replication without eradication of HIV-1.
Enhanced recovery of transformants of Agrobacterium tumefaciens after freeze-thaw transformation and drug selection. (1994)

Freeze-thaw transformation provides a simple and rapid method to transform Agrobacterium tumefaciens directly with plasmid DNA. Competent A. tumefaciens cells of strains LBA4404, GV3850 and EHA101 were transformed with four to nine plasmids differing in size, size of insert and in some cases sensitivity to antibiotics. A threefold to fourfold increase in transformed colonies per microgram of DNA was obtained by freezing cells with liquid nitrogen vs. dry ice/ethanol. Freezing cells in liquid nitrogen followed by incubation of transformed cells in a low concentration of appropriate antibiotics prior to plating resulted in a ninefold increase in colonies obtained compared with the procedure of freezing cells in dry ice/ethanol without the incubation period in the low concentration of antibiotics prior to plating. Restriction fragments of the expected sizes from the plasmids indicated that the procedural modifications did not cause apparent recombinations in the region of the inserts.
Cyclobenzaprine: a new look at an old pharmacological agent (2009)

Cyclobenzaprine is a tricyclic pharmacologic agent that has enjoyed considerable use since its availability. Most clinical usages have focused on the muscle relaxant properties, the mechanism of action being more recently redefined. Higher orders of the CNS are, nevertheless, affected, and the latter contributes to the spectrum of proclaimed side effects that are otherwise largely anticholinergic in nature. Cyclobenzaprine has a reasonable safety profile and overdoses are not as problematic as those for accepted tricyclic psychotherapeutic agents. Clinical studies have given supportive, albeit not conclusive, evidence for treatment roles in the short-term management of acute neck and back pain, and fibromyalgia. Further and more exacting science is warranted to explore the value of this drug in other neurological and psychiatric contexts.
Pancreatic adenocarcinoma—Genetic portrait from chromosomes to microarrays (2006)

Pancreatic adenocarcinoma is the fifth leading cause of cancer death with a 5-year survival rate of less than 5%. Although the role of a few known oncogenes and tumor suppressor genes in the development of pancreatic cancer is fairly well established, it is obvious that the majority of genetic changes responsible for the initiation and progression of this disease are still unknown. In this review, the authors will discuss the results from various genome-wide screening efforts, from traditional chromosome analyses to modern DNA microarray studies, which have provided an enormous amount of information on genetic alterations in pancreatic adenocarcinoma. Exciting findings have emerged from these studies, highlighting multiple potential chromosomal regions that may harbor novel cancer genes involved in the molecular pathogenesis of this lethal disorder. These findings complete the picture of pancreatic adenocarcinoma as a genetically highly complex and heterogeneous tumor type with an ongoing instability process. In addition, the precisely localized copy number changes offer a valuable starting point for further studies required to identify the genes involved and to characterize their potential functional role in the development and progression of pancreatic adenocarcinoma.
Detecting Non-Abelian Statistics in theν=5/2Fractional Quantum Hall State (2006)

In this Letter we propose an interferometric experiment to detect non-Abelian quasiparticle statistics--one of the hallmark characteristics of the Moore-Read state expected to describe the observed fractional quantum Hall effect plateau at nu = 5/2. The implications for using this state for constructing a topologically protected qubit as has been recently proposed by Das Sarma et al. are also addressed.
Role of Glycogen Synthase Kinase-3β in Neuronal Apoptosis Induced by Trophic Withdrawal (2000)

Glycogen synthase kinase-3beta (GSK3beta) activity is negatively regulated by several signal transduction cascades that protect neurons against apoptosis, including the phosphatidylinositol-3 kinase (PI-3 kinase) pathway. This suggests the interesting possibility that activation of GSK3beta may contribute to neuronal apoptosis. Consequently, we evaluated the role of GSK3beta in apoptosis in cultured cortical neurons induced by trophic factor withdrawal or by PI-3 kinase inhibition. Neurons were subjected to several apoptotic paradigms, including serum deprivation, serum deprivation combined with exposure to NMDA receptor antagonists, or treatment with PI-3 kinase inhibitors. These treatments all led to stimulation of GSK3beta activity in cortical neurons, which preceded the induction of apoptosis. Expression of an inhibitory GSK3beta binding protein or a dominant interfering form of GSK3beta reduced neuronal apoptosis, suggesting that GSK3beta contributes to trophic factor withdrawal-induced apoptosis. Furthermore, overexpression of GSK3beta in neurons increased apoptosis, indicating that activation of this enzyme is sufficient to trigger programmed cell death. Although destabilization of beta-catenin is an important physiological effect of GSK3beta activation, expression of a mutant beta-catenin that is not destabilized by GSK3beta did not protect against apoptosis. We conclude that inhibition of GSK3beta is one of the mechanisms by which PI-3 kinase activation protects neurons from programmed cell death.
Experimental study on electrochemical treatment of cancer in mice. (1994)

Electrochemical treatment of cancers in mice resulted in at least partial regression or disappearance of transplanted SRS solid tumours and increased the survival time. Six days after treatment, lymphocyte infiltration in the tumour tissue was found. Seventy-one days after treatment, tumour cells were rarely found in the tissue. The application of direct current was found to facilitate the destruction of tumour cells in a shear stress field.