gebhart/patrepeval huggingface dataset:
Transgenic nonhuman primates for neurodegenerative diseases (2004)

Animal models that represent human diseases constitute an important tool in understanding the pathogenesis of the diseases, and in developing effective therapies. Neurodegenerative diseases are complex disorders involving neuropathologic and psychiatric alterations. Although transgenic and knock-in mouse models of Alzheimer's disease, (AD), Parkinson's disease (PD) and Huntington's disease (HD) have been created, limited representation in clinical aspects has been recognized and the rodent models lack true neurodegeneration. Chemical induction of HD and PD in nonhuman primates (NHP) has been reported, however, the role of intrinsic genetic factors in the development of the diseases is indeterminable. Nonhuman primates closely parallel humans with regard to genetic, neuroanatomic, and cognitive/behavioral characteristics. Accordingly, the development of NHP models for neurodegenerative diseases holds greater promise for success in the discovery of diagnoses, treatments, and cures than approaches using other animal species. Therefore, a transgenic NHP carrying a mutant gene similar to that of patients will help to clarify our understanding of disease onset and progression. Additionally, monitoring disease onset and development in the transgenic NHP by high resolution brain imaging technology such as MRI, and behavioral and cognitive testing can all be carried out simultaneously in the NHP but not in other animal models. Moreover, because of the similarity in motor repertoire between NHPs and humans, it will also be possible to compare the neurologic syndrome observed in the NHP model to that in patients. Understanding the correlation between genetic defects and physiologic changes (e.g. oxidative damage) will lead to a better understanding of disease progression and the development of patient treatments, medications and preventive approaches for high risk individuals. The impact of the transgenic NHP model in understanding the role which genetic disorders play in the development of efficacious interventions and medications is foreseeable.
Interaction of copper(II) and nickel(II) with L-histidine and glycylglycyl-L-histidine as an albumin model (1980)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTInteraction of copper(II) and nickel(II) with L-histidine and glycylglycyl-L-histidine as an albumin modelTakeshi Sakurai and Akitsugu NakaharaCite this: Inorg. Chem. 1980, 19, 4, 847–853Publication Date (Print):April 1, 1980Publication History Published online1 May 2002Published inissue 1 April 1980https://pubs.acs.org/doi/10.1021/ic50206a012https://doi.org/10.1021/ic50206a012research-articleACS PublicationsRequest reuse permissionsArticle Views374Altmetric-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-Alertsclose Get e-Alerts
Probing the Binding Behavior and Conformational States of Globular Proteins in Reversed-Phase High-Performance Liquid Chromatography (1999)

Reversed-phase high-performance liquid chromatography (RP-HPLC) is a widely used technique for the separation of proteins under low pH aquo-organic solvent gradient elution conditions, typically carried out at ambient temperatures. These conditions can however induce conformational effects with proteins as evident from changes in their biological or immunological activities. By monitoring the influence of temperature on the retention and band-broadening characteristics of proteins, the role of conformational processes in these lipophilic environments can be examined. These processes can then be interpreted in terms of a two-state model involving a native (N) and a fully unfolded species (U) or more complex folding/unfolding models. In the present study, the gradient elution RP-HPLC behavior of sperm whale myoglobin (SWMYO) and hen egg white lysozyme (HEWL) has been investigated at temperatures between 5 and 85 degrees C with n-octadecyl (C18)- and n-butyl (C4)-silica reversed-phase sorbents. The interaction of these proteins with these reversed-phase sorbents has also been examined in terms of the contributions that the heme prosthetic group of SWMYO and the disulfide bonds in HEWL make to the stabilization of the native conformation of these proteins in these hydrophobic environments. The observed interconversions of multiple peak zones of SWMYO and HEWL in the presence of C18 and C4 ligands have been subsequently analyzed in terms of the unfolding processes that these proteins can undergo at low pH and at elevated temperatures. The ability of hydrocarbonaceous ligands to trap ensemblies of partially unfolded conformational intermediates of proteins in these perturbing environments has been examined. Pseudo-first-order rate constants have been derived for these processes from analysis of the dependencies on time of the concentration of the different protein species at specified temperatures. The relationship of these processes to the conformational transitions that these proteins can undergo via molten globule-like intermediates (i.e., compact denatured states with a significant amount of residual secondary structure) in solution has also been examined. This study thus further documents an experimental strategy to assess the folding/unfolding behavior of globular proteins in the presence of hydrophobic surfaces and aquo-organic solvents, whereby the system parameters can potentially affect the preservation of native conformations, and thus the function, of the protein under these conditions.
Computer-Assisted Orthopedic Surgery (Caos) (1999)

From the Publisher:
This is a review of the rapidly emerging computer assisted technologies that are starting to fundamentally influence the way that we design, plan, simulate, and carry out orthopedic surgery. This volume provides an overview of the state-of-the-art of the development of CAOS and its clinical applications. Topics covered range from basic concepts to planning, simulation and execution of surgery in different anatomical areas, including the spine, hip and knee. Various surgical techniques, such as joint reconstruction and replacement, trauma fixation, and minimally invasive approaches are also presented.
Polymerase chain reaction in the diagnosis of bacterial endophthalmitis (1998)

PCR performed on AH and VF is a reliable tool for the diagnosis of bacterial and P acnes endophthalmitis particularly in smear and culture negative specimens.
Polar zipper sequence in the high-affinity hemoglobin of Ascaris suum: amino acid sequence and structural interpretation. (1992)

The extracellular hemoglobin of Ascaris has an extremely high oxygen affinity (P50 = 0.004 mmHg). It consists of eight identical subunits of molecular weight 40,600. Their sequence, determined by protein chemistry, shows two tandemly linked globin-like sequences and an 18-residue C-terminal extension. Two N-linked glycosylation sites contain equal ratios of mannose/glucosamine/fucose of 3:2:1. Electron micrographs suggest that the eight subunits form a polyhedron of point symmetry D4, or 42. The C-terminal extension contains a repeat of the sequence Glu-Glu-His-Lys, which would form a pattern of alternate glutamate and histidine side chains on one side and of glutamate and lysine side chains on the other side of a beta strand. We propose that this represents a polar zipper sequence and that the C-terminal extensions are joined in an eight-stranded beta barrel at the center of the molecule, with histidine and glutamate side chains inside and lysine and glutamate side chains outside the barrel compensating each other's charges. The amino acid sequence of Ascaris hemoglobin fails to explain its high oxygen affinity.
Pharmacogenomics of Adverse Drug Reactions: Practical Applications and Perspectives (2009)

Serious adverse drug reactions represent the sixth major cause of death in the USA, are the main reason for postmarketing drug withdrawal and represent billions of US dollars in costs every year in all developed countries. Some of these serious adverse drug reactions might be avoided by systematically screening for pharmacogenomic risk factors. During the last few years, regulatory agencies introduced pharmacogenomics labels for several drugs, but although a priori genetic testing remains advised or recommended, it is seldom compulsory due to poor evidence-based medicine knowledge. Recently published pharmacogenomic randomized, controlled and ongoing trials will progressively make genotyping tests, such as those for HLA-B*5701 (abacavir), TPMT (6-mercaptopurine), CYP2C9 plus VKORC1 (warfarin) and CYP3A5 (tacrolimus), mandatory. Parallel development of pharmacogenomic bed tests will certainly establish genetically-based prescriptions in routine medical practice.
Chemokine Antagonists That Discriminate between Interleukin-8 Receptors (1997)

Human neutrophils express two interleukin (IL)-8 receptors, CXC chemokine receptor (CXCR) 1 and CXCR2. IL-8 with changes to the NH2-terminal ELR motif can block IL-8-induced neutrophil functions (Moser, B., Dewald, B., Barella, L., Schumacher, C., Baggiolini, M., and Clark-Lewis, I. (1993) J. Biol. Chem. 268, 7125-7128). We have now examined the effect of NH2-terminally modified analogs of IL-8, GROalpha, and PF4 on CXCR1 and CXCR2 independently. Using stable Jurkat transfectants expressing either CXCR1 or CXCR2, it was shown that analogs derived from IL-8 bound both IL-8 receptors with similar affinity and could block IL-8-induced Ca2+ mobilization. By contrast, analogs of GROalpha and PF4, (R)GROalpha and (R)PF4, bound only CXCR2 with high affinity and blocked Ca2+ mobilization induced only via CXCR2. The differential effect on CXCR1 and CXCR2 was also demonstrated in studies with isolated neutrophils. Thus (R)GROalpha and (R)PF4 inhibited only the GROalpha but not the IL-8-stimulated elastase release, and these two analogs had no effect on IL-8-elicited superoxide generation, a response that is mediated by CXCR1 but not by CXCR2. These results show that CXCR2 selective receptor antagonists can be generated based upon the secondary binding determinants of GROalpha and PF4. They also highlight the primary importance of CXCR1 in chemokine-mediated release of granule enzymes and superoxide generation. The selective antagonists described may be used in future studies on IL-8 receptor signaling to define distinct steps leading to various functional responses induced in neutrophils via CXCR1 and CXCR2.
AKT-Independent Protection of Prostate Cancer Cells from Apoptosis Mediated through Complex Formation between the Androgen Receptor and FKHR (2002)

Recent studies suggested that the protection of cell apoptosis by AKT involves phosphorylation and inhibition of FKHR and related FOXO forkhead transcription factors and that androgens provide an AKT-independent cell survival signal in prostate cancer cells. Here, we report receptor-dependent repression of FKHR function by androgens in prostate cancer cells. Transcriptional analysis demonstrated that activation of the androgen receptor caused an inhibition of both wild-type FKHR and a mutant in which all three known AKT sites were mutated to alanines, showing that the repression is AKT independent. In vivo and in vitro coprecipitation studies demonstrated that the repression is mediated through protein-protein interaction between FKHR and the androgen receptor. Mapping analysis localized the interacting domains to the carboxyl terminus between amino acids 350 and 655 of FKHR and to the amino-terminal A/B region and the ligand binding domain of the receptor. Further analysis demonstrated that the activated androgen receptor blocked FKHR's DNA binding activity and impaired its ability to induce Fas ligand expression and prostate cancer cell apoptosis and cell cycle arrest. These studies identify a new mechanism for androgen-mediated prostate cancer cell survival that appears to be independent of the activity of the receptor on androgen response element-mediated transcription and establish FKHR and related FOXO forkhead proteins as important nuclear targets for both AKT-dependent and -independent survival signals in prostate cancer cells.
The Facile and Efficient Three-Component One-Pot Mannich-Type Reaction of Indoles Catalyzed by In(OTf)3 Under Microwave Irradiations (2008)

Indium triflate catalysed the three-component one-pot reaction of indole 1 with a heteroimine generated in situ under microwave irradiations and afforded predominately secondary indolyl amines 4 in excellent yields as well as bisindolyl methane 5 in poor yields. The catalyst indium triflate can be recovered after the reaction and reused in the subsequent experiments. Keywords: Indoles, indium triflate, microwave irradiations, multicomponent reactions, Mannich-type reactions, bisindolyl methane
The economic background [December 1995] (1995)

Exports are of critical importance to the Scottish Economy. In 1989, Scottish firms sold goods and services worth £64.7bn to final users, of which 21'/2% were to customers in the rest of the UK (RUK) and 14.7% to overseas (ROW) clients. In the case of manufacturing, final sales totalled £25.4bn, of which 35.3% were due to RUK and 32.5% to the ROW. Thus, two thirds of Scottish manufactured goods were sold out with Scotland illustrating the importance of non domestic markets to Scottish incomes and employment.
Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade (2016)

Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti-PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti-PD-1/PD-L1. Cancer Immunol Res; 4(11); 959-67. ©2016 AACR.
Increased interleukin-17 production in patients with systemic sclerosis (2000)

IL-17 is overproduced by T cells from the peripheral blood and fibrotic lesions of the skin and lungs in SSc patients. These results suggest that IL-17 overproduction plays an important role in the pathogenesis of SSc, especially in the early stages of the disease, by inducing the proliferation of fibroblasts and the production of IL-1 and the expression of adhesion molecules on endothelial cells.
Two-Stage, Pipelined Register Renaming (2010)

Register renaming is a performance-critical component of modern, dynamically-scheduled processors. Register renaming latency increases as a function of several architectural parameters (e.g., processor issue width, processor window size, and processor checkpoint count). Pipelining of the register renaming logic can help avoid restricting the processor clock frequency. This work presents a full-custom, two-stage register renaming implementation in a 130-nm fabrication technology. The latency of non-pipelined and two-stage, pipelined renaming is compared, and the underlying performance and complexity tradeoffs are discussed. The two-stage pipelined design reduces the renaming logic depth from 23 fan-out-of-four (FO4) down to 9.5 FO4.
A solid-state deuterium NMR investigation of conformation and order in magnetically oriented [d(CGCGAATTCGCG)]2 (1990)

Solid-state deuterium NMR has been used to investigate the oriented liquid crystal phase of the hydrated oligonucleotide [d(CGCGAATTCGCG)]2. Previous investigations have shown that the helix axis is aligned perpendicular to the magnetic field, while at reduced temperatures motion about the helix axis is eliminated. Synthetic oligonucleotide samples incorporating different labeled nucleosides, [2"-2H]-2'-deoxyadenosine, [methyl-2H]thymidine, [8-2H]-2'-deoxyguanosine, and [8-2H]-2'-deoxyadenosine, permitted investigation of both the base and sugar conformation and ordering in the aligned phase. From line-shape analysis of the purine-labeled samples the orientation of the base C8 C-D bond with respect to the helix axis was determined to be theta = 90 degrees with a distribution of sigma total = 20 degrees, which is comparable to the orientation of theta = 90 degrees, sigma total = 15 degrees, with an oriented fraction P = 0.7 found for the C3 symmetry axis of the methyl-labeled dodecamer. The orientation of the sugar 2" C-D bond with respect to the helix axis is theta = 22 degrees with a distribution of sigma total = 15 degrees in agreement with the expected C2'-endo sugar conformation. The fraction of C3'-endo was also investigated and from analysis of line shape cannot exceed 20%. These results, though preliminary in nature, illustrate the application of this aligned phase for structural investigations.
Fibronectin self-association is mediated by complementary sites within the amino-terminal one-third of the molecule. (1994)

The formation of a fibrillar fibronectin (FN) extracellular matrix requires self-association of FN dimers. In this report, we show that the major sites for self-association are the amino-terminal repeats I1-5 and the first type III repeats. Recombinant FNs and fragments were generated by baculovirus expression of cysteine-rich domains and by bacterial expression of type III repeats as fusion proteins with maltose binding protein. When recombinant polypeptides were immobilized on microtiter wells, FN bound to 70-kDa amino-terminal fragment and to fusion proteins containing repeats III1-2 and III1-6 but not to other type III repeats. Similar results were obtained with a gel overlay assay. Binding was concentration-dependent and saturable. The amino-terminal binding site for III1-2 was further localized to repeats I1-5. Therefore, at least two different sites for FN-FN interaction reside near the amino terminus of the molecule. A model for the regulation of FN matrix assembly is proposed based on intramolecular interactions between these amino-terminal sites.
Endogenous cholecystokinin and intestinal satiety (1985)

The role of endogenous cholecystokinin (CCK) as a mediator of intestinal satiety is examined. We used rats equipped with a chronic gastric fistula and an indwelling duodenal catheter to assess the effects of direct duodenal stimulation on sham feeding. To evaluate the contribution of endogenous CCK to intestinal satiety we used a specific competitive antagonist of the satiety action of CCK, proglumide. Intraduodenal infusion of 11 or 5 ml liquid diet suppressed sham feeding. Administration of proglumide caused a partial reversal of the suppression of feeding produced by the 11-ml, but not the 5-ml, intraduodenal infusion. Administration of proglumide alone did not influence sham feeding but completely abolished the suppression of sham feeding induced by a maximal dose of exogenous CCK. These results indicate that CCK contributes to intestinal satiety under specific test conditions only. Moreover, since that component of suppression reversed by proglumide was small in comparison with the overall inhibition of eating, these results indicate that factors other than CCK are important in intestinal satiety.
TREATMENT OF INTRACTABLE BRONCHIAL ASTHMA BY BILATERAL RESECTION OF THE POSTERIOR PULMONARY PLEXUS (1938)

Although it is relatively small, there exists a group of patients afflicted with typical bronchial seizures which are unamenable to medicinal therapy. It is to the amelioration of these attacks in such patients that our attention has been drawn. Only cases of unquestionable bronchial asthma have been selected, and only patients totally incapacitated physically have been subjected to operation. The rationale of the procedure of bilateral resection of the posterior pulmonary plexus is based on the anatomic fact that only at this point can the extrinsic nerve supply of the lung be completely interrupted. The preganglionic efferent fibers of both the vagus and the sympathetic bronchomotor tracts from the same and contralateral sides, together with the sensory or afferent fibers emerging from the lung, form a rather limited anastomosing plexus on the posterior surface of the hilus of the lung. By resection of this plexus it is therefore possible to
Tracking lineages of single cells in lines using a microfluidic device (2009)

Cells within a genetically identical population exhibit phenotypic variation that in some cases can persist across multiple generations. However, information about the temporal variation and familial dependence of protein levels remains hidden when studying the population as an ensemble. To correlate phenotypes with the age and genealogy of single cells over time, we developed a microfluidic device that enables us to track multiple lineages in parallel by trapping single cells and constraining them to grow in lines for as many as 8 divisions. To illustrate the utility of this method, we investigate lineages of cells expressing one of 3 naturally regulated proteins, each with a different representative expression behavior. Within lineages deriving from single cells, we observe genealogically related clusters of cells with similar phenotype; cluster sizes vary markedly among the 3 proteins, suggesting that the time scale of phenotypic persistence is protein-specific. Growing lines of cells also allows us to dynamically track temporal fluctuations in protein levels at the same time as pedigree relationships among the cells as they divide in the chambers. We observe bursts in expression levels of the heat shock protein Hsp12-GFP that occur simultaneously in mother and daughter cells. In contrast, the ribosomal protein Rps8b-GFP shows relatively constant levels of expression over time. This method is an essential step toward understanding the time scales of phenotypic variation and correlations in phenotype among single cells within a population.