gebhart/patrepeval huggingface dataset:
Congenital hyperinsulinism: current status and future perspectives (2014)

The diagnosis and treatment of congenital hyperinsulinism (CHI) have made a remarkable progress over the past 20 years and, currently, it is relatively rare to see patients who are left with severe psychomotor delay. The improvement was made possible by the recent developments in the understanding of the molecular and pathological basis of CHI. Known etiologies include inactivating mutations of the KATP channel genes (ABCC8 and KCNJ11) and HNF4A, HNF1A, HADH, and UCP2 or activating mutations of GLUD1, GCK, and SLC16A1. The understanding of the focal form of KATP channel CHI and its detection by (18)F-fluoro-L-DOPA positron emission tomography have revolutionized the management of CHI, and many patients can be cured without postoperative diabetes mellitus. The incidence of the focal form appears to be higher in Asian countries; therefore, the establishment of treatment systems is even more important in this population. In addition to diazoxide or long-term subcutaneous infusion of octreotide or glucagon, long-acting octreotide or lanreotide have also been used successfully until spontaneous remission. Because of these medications, near-total pancreatectomy is less often performed even for the diazoxide-unresponsive diffuse form of CHI. Other promising medications include pasireotide, small-molecule correctors such as sulfonylurea or carbamazepine, GLP1 receptor antagonists, or mammalian target of rapamycin inhibitors. Unsolved questions in this field include the identification of the remaining genes responsible for CHI, the mechanisms leading to transient CHI, and the mechanisms responsible for the spontaneous remission of CHI. This article reviews recent developments and hypothesis regarding these questions.
Stabilization of Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Trimers by Disulfide Bonds Introduced into the gp41 Glycoprotein Ectodomain (1998)

Biochemical and structural studies of fragments of the ectodomain of the human immunodeficiency virus type 1 (HIV-1) gp41 transmembrane envelope glycoprotein have demonstrated that the molecular contacts between alpha helices allow the formation of a trimeric coiled coil. By introducing cysteine residues into specific locations along these alpha helices, the normally labile HIV-1 gp160 envelope glycoprotein was converted into a stable disulfide-linked oligomer. Although proteolytic cleavage into gp120 and gp41 glycoproteins was largely blocked, the disulfide-linked oligomer was efficiently transported to the cell surface and was recognized by a series of conformationally dependent antibodies. The pattern of hetero-oligomer formation between this construct and an analogous construct lacking portions of the gp120 variable loops and of the gp41 cytoplasmic tail demonstrates that these oligomers are trimers. These results support the relevance of the proposed gp41 structure and intersubunit contacts to the native, complete HIV-1 envelope glycoprotein. Disulfide-mediated stabilization of the labile HIV-1 envelope glycoprotein oligomer, which has been suggested to possess advantages as an immunogen, may assist attempts to develop vaccines.
Structure-based approach to the prediction of disulfide bonds in proteins (2014)

Protein engineering remains an area of growing importance in pharmaceutical and biotechnology research. Stabilization of a folded protein conformation is a frequent goal in projects that deal with affinity optimization, enzyme design, protein construct design, and reducing the size of functional proteins. Indeed, it can be desirable to assess and improve protein stability in order to avoid liabilities such as aggregation, degradation, and immunogenic response that may arise during development. One way to stabilize a protein is through the introduction of disulfide bonds. Here, we describe a method to predict pairs of protein residues that can be mutated to form a disulfide bond. We combine a physics-based approach that incorporates implicit solvent molecular mechanics with a knowledge-based approach. We first assign relative weights to the terms that comprise our scoring function using a genetic algorithm applied to a set of 75 wild-type structures that each contains a disulfide bond. The method is then tested on a separate set of 13 engineered proteins comprising 15 artificial stabilizing disulfides introduced via site-directed mutagenesis. We find that the native disulfide in the wild-type proteins is scored well, on average (within the top 6% of the reasonable pairs of residues that could form a disulfide bond) while 6 out of the 15 artificial stabilizing disulfides scored within the top 13% of ranked predictions. Overall, this suggests that the physics-based approach presented here can be useful for triaging possible pairs of mutations for disulfide bond formation to improve protein stability.
Influence of tyrosine and phenylalanine limitation on cytotoxicity of chimeric TGF‐α toxins on B16Bl6 murine melanomain vitro (1998)

Previous research in animals supports the use of tyrosine and phenylalanine (Tyr-Phe) restriction as an adjuvant to the treatment of cancer. In this regard, dietary restriction of Tyr-Phe specifically inhibits the growth of B16BL6 melanoma tumors, dramatically suppresses spontaneous hematogenous metastasis, and modulates the sensitivity of these tumor cells to growth factors. Two chimeric toxins, HB-TGF alpha-PE4EKDEL and TGF alpha-PE4EKDEL, were examined for their toxicity against the B16BL6 melanoma cell line, and the ability of Tyr-Phe limitation to modulate the potential of these toxins was examined. Tyr-Phe limitation significantly enhanced the cytotoxic effects of HB-TGF alpha-PE4EKDEL approximately 10-fold toward B16BL6 melanoma, and free heparin diminished the cytotoxicity of HB-TGF alpha-PE4EKDEL. Although TGF alpha-PE4EKDEL is cytotoxic to this cell line, Tyr-Phe limitation did not effect the cytotoxicity of this toxin. Tyr-Phe limitation inhibited the synthesis and secretion of heparin-binding proteins but did not alter the expression of surface heparan sulfate proteoglycans. These data suggest that cell surface heparan sulfate proteoglycan is a target for binding and execution of the cytotoxicity of HB-TGF alpha-PE4EKDEL and that augmentation of cytotoxicity by Tyr-Phe limitation is due to the inhibition of heparin-binding protein production.
Co-Interaction and Increased Release of Tissue Factor Pathway Inhibitor by Heparanase. (2005)

Abstract Background and objectives. Tissue factor pathway inhibitor (TFPI) is a potent direct inhibitor of factor Xa and factor VIIa-tissue factor complex. In addition, TFPI was shown to be an inhibitor of angiogenesis and metastasis. Heparanase is an endo-beta-D-glucuronidase of 65 kDa that cleaves heparan sulfate chains on cell surfaces and in the extra-cellular matrix an activity that closely correlates with cell invasion, angiogenesis and tumor growth. The study hypothesis was that heparanase may reduce the level of TFPI or release it from the cell surface in an attempt to increase heparanase prometastatic potential. Material and methods. The effect of exogenous heparanase on TFPI expression and release to the medium was studied in HUVEC by immunoblotting, real time RT-PCR, and flow-cytometry. Human cell lines (MDA-MB-435 breast carcinoma; U87 glioma; HEK-293 embryonic kidney) were transfected to over express heparanase and the effect on TFPI was studied. TFPI expression was explored in heparanase transgenic mice by immunoblotting and immunostaining. Transfections with various modified forms of heparanase were used to further explore the effect of heparanase. Interaction between TFPI and heparanase was studied by co-immunoprecipitation analysis. Results. Heparanase was found to increase the release of TFPI to the medium, reduce the level of TFPI at the cell surface, and to up-regulate its expression in the cells. These results were verified in HUVEC, tumor cell lines, and in the animal model. The effect was independent of heparanase activity or interaction with heparan sulfate, and dependent on heparanase secretion. A protein co-interaction between TFPI and heparanase was found. Conclusions. Overall, a cell surface interaction is suggested in which heparanase impose increased release of TFPI from the cell surface to the medium, providing a local procoagulant and a systemic anticoagulant environment.
Ion Drag Pumps (1960)

The behavior and the efficiency of a simplified model of an ion drag pump for insulating fluids is discussed theoretically. Supporting measurements on real pumps are reported. Cascading and paralleling of pumping stages is investigated.
Pulsed force sequences for fast phase-insensitive quantum gates in trapped ions (2014)

We show how to create quantum gates of arbitrary speed between trapped ions using a laser walking wave, with complete insensitivity to the drift of the optical phase, and requiring cooling only to the Lamb–Dicke regime. We present pulse sequences that satisfy the requirements and are easy to produce in the laboratory.
Bacterial peptidoglycan-derived molecules activateCandida albicanshyphal growth (2008)

Serum strongly induces the yeast-to-hypha growth transition in the human fungal pathogen Candida albicans, playing an important role in infection. However, identity of the serum inducer(s) and its sensor remain poorly defined. We used NMR to analyze the chromatographic serum fractionations enriched for the hypha-inducing activity and found structures resembling subunits of bacterial peptidoglycan (PGN). We then confirmed that several purified and synthetic muramyl dipeptides (MDPs), subunits of PGN, can indeed strongly promote C. albicans hyphal growth. Taking cue from the recognition of MDPs by the mammalian bacterial sensor Nod2 using its leucine-rich-repeat (LRR) domain, we discovered that MDPs activate the adenylyl cyclase Cyr1 by binding to its LRR domain. The cAMP/PKA signaling pathway is well known to control hyphal morphogenesis and other infection-related traits. Given the abundance of PGN at the large intestinal epithelial surface, a natural habitat and invasion site for C. albcians, our findings have important implications in the mechanisms of infection by this pathogen.
Neural networks for optimization and signal processing (1993)

From the Publisher:
Artificial neural networks can be employed to solve a wide spectrum of problems in optimization, parallel computing, matrix algebra and signal processing. Taking a computational approach, this book explains how ANNs provide solutions in real time, and allow the visualization and development of new techniques and architectures. Features include a guide to the fundamental mathematics of neurocomputing, a review of neural network models and an analysis of their associated algorithms, and state-of-the-art procedures to solve optimization problems. Computer simulation programs MATLAB, TUTSIM and SPICE illustrate the validity and performance of the algorithms and architectures described. The authors encourage the reader to be creative in visualizing new approaches and detail how other specialized computer programs can evaluate performance. Each chapter concludes with a short bibliography. Illustrative worked examples, questions and problems assist self study. The authors' self-contained approach will appeal to a wide range of readers, including professional engineers working in computing, optimization, operational research, systems identification and control theory. Undergraduate and postgraduate students in computer science, electrical and electronic engineering will also find this text invaluable. In particular, the text will be ideal to supplement courses in circuit analysis and design, adaptive systems, control systems, signal processing and parallel computing.
Both lipid environment and pH are critical for determining physiological solution structure of 3‐D‐conserved epitopes of the HIV‐1 gp41‐MPER peptide P1 (2008)

In terms of background, the solution structure of monomeric peptide P1 (residues 649-683), located in the conserved membrane proximal region (MPER) of HIV-1 envelope glycoprotein gp41, is first reported here in dodecylphosphocholine (DPC) micelles. P1 is the minimal MPER region that permits interaction with the mucosal galactosyl ceramide HIV-receptor; it also contains epitopes recognized by major gp41-specific, broadly neutralizing immunoglobulin Gs (IgGs), 2F5 and 4E10, determinant in HIV fusion/infection. Our principal findings were as follows: the structural stability of P1 is pH dependent, as the alpha-helix comprising Q653 I682, present at pH 3.3, is destabilized at higher pH values. At pH 6, the E-rich N-terminal half of P1 (residues 650-666), partially overlapping the 2F5-specific epitope, becomes fully disordered, while the W-rich C-terminal half conserves two shorter helices (W666-W670 and W672-W680), separated by a well-defined bend overlapped by the 4E10-specific epitope. The two IgGs bind to P1 on DPC micelles with binding parameters (K(d)) in the nanomolar range. Next, P1 was derivatized with phosphatidylethanolamine at its C terminal and inserted into liposomes of varied lipid composition, thereby enabling P1 to move laterally. Alternatively, an infectious virus-binding assay was established. The K(d) of both 2F5 and 4E10 IgGs measured on viral liposome and virus are similar and much lower than for the binding of the free peptide. In conclusion, P1, in a lipid environment, is an optimized MPER-derived peptide suitable for designing an immunogen inducing broadly neutralizing antibodies to HIV.
Metabolic Alarms and Cell Division in Escherichia coli (1999)

Cells respond to a variety of signals, adapting their behavior and pattern of gene expression as a function of the situation. In Escherichia coli , the reactions to environmental stresses—heat shock, starvation, and the like—have been termed global responses. During gradual changes, such as the
Site-directed mutagenesis of the catalytic residues Asp-52 and Glu-35 of chicken egg white lysozyme. (1989)

The roles of the catalytic active-site residues aspartic acid-52 and glutamic acid-35 of chicken lysozyme (EC 3.2.1.17) have been investigated by separate in vitro mutagenesis of each residue to its corresponding amide (denoted as D52N and E35Q, respectively). The mutant enzyme D52N exhibits approximately 5% of the wild-type lytic activity against Micrococcus luteus cell walls, while there is no measurable activity associated with E35Q (0.1% +/- 0.1%). The measured dissociation constants for the chitotriose-enzyme complexes were 4.1 microM (D52N) and 13.4 microM (E35Q) vs. 8.6 microM for wild type, indicating that the alterations in catalytic properties may be due in part to binding effects as well as to direct catalytic participation of these residues. The mutant lysozymes have been expressed in and secreted from yeast and obtained at a level of approximately 5 mg per liter of culture by high-salt elution from the cell walls.
Complex Regulation of the Yeast Heat Shock Transcription Factor (2000)

The yeast heat shock transcription factor (HSF) is regulated by posttranslational modification. Heat and superoxide can induce the conformational change associated with the heat shock response. Interaction between HSF and the chaperone hsp70 is also thought to play a role in HSF regulation. Here, we show that the Ssb1/2p member of the hsp70 family can form a stable, ATP-sensitive complex with HSF-a surprising finding because Ssb1/2p is not induced by heat shock. Phosphorylation and the assembly of HSF into larger, ATP-sensitive complexes both occur when HSF activity decreases, whether during adaptation to a raised temperature or during growth at low glucose concentrations. These larger HSF complexes also form during recovery from heat shock. However, if HSF is assembled into ATP-sensitive complexes (during growth at a low glucose concentration), heat shock does not stimulate the dissociation of the complexes. Nor does induction of the conformational change induce their dissociation. Modulation of the in vivo concentrations of the SSA and SSB proteins by deletion or overexpression affects HSF activity in a manner that is consistent with these findings and suggests the model that the SSA and SSB proteins perform distinct roles in the regulation of HSF activity.
Long-term testing in a short-term world (2003)

Accelerated stress testing reduces the time required to test a system but can be hard to apply to functions running on a fixed schedule. This article describes how to accelerate the testing of scheduled functions by triggering them through automated tests, either by periodically advancing the system clock or through a programmatic event interface. With this method, the accelerated stress tests don't distort the system's operational profile.
DOE/Allison ceramic vane effort (1995)

An objective of the Advanced Turbine Systems (ATS) program is to develop ultra-high efficiency gas turbine systems. Rotor inlet temperatures several hundred degrees greater than for the highest temperature current industrial engines will be required to meet the ATS objectives. Consequently, new technologies need to be developed and demonstrated to achieve the required ultra-high ATS efficiencies.
Protective Antibody Responses Elicited by a Meningococcal Outer Membrane Vesicle Vaccine with Overexpressed Genome‐Derived Neisserial Antigen 1870 (2005)

Background. Meningococcal outer membrane vesicle (OMV) vaccines are efficacious in humans but have serosubtype-specific serum bactericidal antibody responses directed at the porin protein PorA and the potential for immune selection of PorA-escape mutants.Methods. We prepared an OMV vaccine from a Neisseria meningitidis strain engineered to overexpress genome-derived neisserial antigen (GNA) 1870, a lipoprotein discovered by genome mining that is being investigated for use in a vaccine.Results. Mice immunized with the modified GNA1870-OMV vaccine developed broader serum bactericidal antibody responses than control mice immunized with a recombinant GNA1870 protein vaccine or an OMV vaccine prepared from wild-type N. meningitidis or a combination of vaccines prepared from wild-type N. meningitidis and recombinant protein. Antiserum from mice immunized with the modified GNA1870-OMV vaccine also elicited greater deposition of human C3 complement on the surface of live N. meningitidis bacteria and greater passive protective activity against meningococcal bacteremia in infant rats. A N. meningitidis mutant with decreased expression of PorA was more susceptible to bactericidal activity of anti-GNA1870 antibodies.Conclusions. The modified GNA1870-OMV vaccine elicits broader protection against meningococcal disease than recombinant GNA1870 protein or conventional OMV vaccines and also has less risk of selection of PorA-escape mutants than a conventional OMV vaccine.
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease (1997)

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.
FoxA1 Binding Directs Chromatin Structure and the Functional Response of a Glucocorticoid Receptor-Regulated Promoter (2009)

Reconstitution of the glucocorticoid receptor (GR)-regulated mouse mammary tumor virus (MMTV) promoter in Xenopus oocytes was used to monitor the effects of different transcription factor contexts. Three constitutively binding factors, nuclear factor 1 (NF1), octamer transcription factor 1 (Oct1), and the Forkhead box A1 (FoxA1), were shown to act in concert, to direct the chromatin structure, and to enhance the GR response. FoxA1 has a dominant effect in the absence of hormone and induces a cluster of DNase I-hypersensitive sites in the segment comprising bp -400 to +25. This FoxA1-mediated chromatin remodeling does not induce MMTV transcription, as opposed to that of the GR. However, the robust FoxA1-dependent chromatin opening has the following drastic functional consequences on the hormone regulation: (i) GR-DNA binding is facilitated, as revealed by dimethyl sulfate in vivo footprinting, leading to increased hormone-induced transcription, and (ii) the GR antagonist RU486 is converted into a partial agonist in the presence of FoxA1 via ligand-independent GR activation. We conclude that FoxA1 mediates a preset chromatin structure and directs a context-specific response of a nuclear receptor. Furthermore, the alternative nucleosome arrangement induced by GR and FoxA1 implies this to be determined by constitutive binding of transcription factors rather than by the DNA sequence itself.
Hydride transfer in the oxidation of formate ion by [(bpy)2(py)Ru(O)]2+ (1986)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHydride transfer in the oxidation of formate ion by [(bpy)2(py)Ru(O)]2+Lee. Roecker and Thomas J. MeyerCite this: J. Am. Chem. Soc. 1986, 108, 14, 4066–4073Publication Date (Print):July 1, 1986Publication History Published online1 May 2002Published inissue 1 July 1986https://pubs.acs.org/doi/10.1021/ja00274a035https://doi.org/10.1021/ja00274a035research-articleACS PublicationsRequest reuse permissionsArticle Views358Altmetric-Citations34LEARN 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 optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts