gebhart/patrepeval huggingface dataset:
Biomarkers for Alzheimer's disease. Where we stand and where we are headed. (2019)

Alzheimer disease (AD) is one of the major unresolved health burdens accompanying the increase in life expectancy. The great paradigm shift for this disease has resulted from finding amyloid deposition and neurobrillary degeneration 20 years and 10 years, respectively, prior to onset of the typical clinical memory loss symptoms. The advent of AD biomarkers has enabled a molecular definition of AD, making the clinical definition almost dispensable. Various types of AD biomarkers are available in our country. Each biomarker reflects a particular process and stage of the disease. Although costs restrict their use, the biomarker analysis may be justified in certain clinical scenarios, such as an early onset or an atypical presentation of the disease. Today, the usefulness of biomarkers in AD clinical research is beyond question. Furthermore, the introduction of biomarkers into medical practice has led to significant changes in therapeutic interventions, even in the absence of disease-modifying drugs.
The structural basis for the transition from Ras-GTP to Ras-GDP (2002)

The conformational changes in Ras that accompany the hydrolysis of GTP are critical to its function as a molecular switch in signaling pathways. Understanding how GTP is hydrolyzed by revealing the sequence of intermediary structures in the reaction is essential for understanding Ras signaling. Until now, no structure of an intermediate in GTP hydrolysis has been experimentally determined for Ras alone. We have solved the crystal structure of the Ala-59 to Gly mutant of Ras, (RasA59G), bound to guanosine 5'-imidotriphosphate or GDP to 1.7-A resolution. In the guanosine 5'-imidotriphosphate-bound form, this mutant adopts a conformation that is intermediate between the GTP- and GDP-bound forms of wild-type Ras and that is similar to what has been predicted by molecular dynamics simulation [Ma, J. P. & Karplus, M. (1997) Proc. Natl. Acad. Sci. USA 94, 11905-11910]. This conformation is stabilized by direct and water-mediated interactions between the switch 1 and switch 2 regions and is characterized by an increase in the binding affinity for GTP. We propose that the structural changes promoted by the Ala-59 to Gly mutation exhibit a discrete conformational state assumed by wild-type Ras during GTP hydrolysis.
Inactivation of the Glucocorticoid Receptor in Hepatocytes Leads to Fasting Hypoglycemia and Ameliorates Hyperglycemia in Streptozotocin-Induced Diabetes Mellitus (2004)

Hepatic glucose production by gluconeogenesis is the main source of glucose during fasting and contributes significantly to hyperglycemia in diabetes mellitus. Accordingly, glucose metabolism is tightly controlled by a variety of hormones including insulin, epinephrine, glucagon, and glucocorticoids (GCs) acting on various cell types. GC effects are mediated by the GC receptor (GR), a ligand-dependent transcription factor, which in the liver and kidney controls gluconeogenesis by induction of gluconeogenic enzymes. To specifically study the contribution of GC on liver carbohydrate metabolism, we generated mice with an inactivation of the GR gene exclusively in hepatocytes using the Cre/loxP technology. Half of the mutant mice die within the first 2 d after birth most likely due to hypoglycemia. Adult mice have normal blood sugar under basal conditions but show hypoglycemia after prolonged starvation due to reduced expression of genes involved in gluconeogenesis. We further demonstrate that absence of GR in hepatocytes limits the development of hyperglycemia in streptozotocin-induced diabetes mellitus probably due to impaired induction of gluconeogenesis. These findings show the essential role of GR function in liver glucose metabolism during fasting and in diabetic mice and indicate that liver-specific GC antagonists could be beneficial in control of diabetic hyperglycemia.
Study of Bias‐Dependent Etching of Si in Aqueous  KOH (1987)

The bias‐dependent etching of Si in has been studied in detail. The quantity of Si etched and evolved has been measured at various anodic and cathodic potentials. These quantities have been related to the current flow in the electrochemical cell in such a way as to shed light on the mechanisms responsible for bias‐dependent etching of Si.
Design and Synthesis of Novel Pyrrolo[2,1-c][1,4]benzodiazepine−Lexitropsin Conjugates (1998)

ADVERTISEMENT RETURN TO ISSUEPREVNoteNEXTDesign and Synthesis of Novel Pyrrolo[2,1-c][1,4]benzodiazepine−Lexitropsin ConjugatesYalamati Damayanthi, B. S. Praveen Reddy, and J. William LownView Author Information Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2 Cite this: J. Org. Chem. 1999, 64, 1, 290–292Publication Date (Web):December 9, 1998Publication History Received22 June 1998Published online9 December 1998Published inissue 1 January 1999https://pubs.acs.org/doi/10.1021/jo9812072https://doi.org/10.1021/jo9812072brief-reportACS PublicationsCopyright © 1999 American Chemical SocietyRequest reuse permissionsArticle Views360Altmetric-Citations36LEARN 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 SUBJECTS:Alkyls,Conjugate acid-base pairs,Ethers,Genetics,Nucleic acid structure Get e-Alerts
Biomimetic ion transport: a functional model of a unimolecular ion channel (1989)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTBiomimetic ion transport: a functional model of a unimolecular ion channelV. E. Carmichael, P. J. Dutton, T. M. Fyles, T. D. James, J. A. Swan, and M. ZojajiCite this: J. Am. Chem. Soc. 1989, 111, 2, 767–769Publication Date (Print):January 1, 1989Publication History Published online1 May 2002Published inissue 1 January 1989https://pubs.acs.org/doi/10.1021/ja00184a075https://doi.org/10.1021/ja00184a075research-articleACS PublicationsRequest reuse permissionsArticle Views550Altmetric-Citations104LEARN 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
Hydroalcoholic Extract of Rosemary (Rosmarinus officinalis L.) and its Constituent Carnosol Inhibit Formalin-induced Pain and Inflammation in Mice (2013)

The anti-inflammatory and anti-nociceptive properties of Rosmarinus officinalis L. (ROL) extract and its major constituent, carnosol in male NMRI mice (W:25-30 g) have been evaluated in the present study. Formalin (2%, 20 microL) was injected into the plantar portion of the hind paw and resulting pain and inflammation was studied for 60 min. The plant extract, carnosol and other drugs were administered intraperitoneally or subcutaneously 30 min before formalin injection. In a separate experiment, the effects of the extract and carnosol on plasma corticosterone levels and activity of the enzymes cyclooxygenase type 1 and 2 (COX1 and COX2) were investigated. Injection of different doses of ROL and carnosol reduced pain in the phase 2 of the formalin test, which was not inhibited by naloxone and/or memantine. In addition, pretreatment of the animals with ROL and/or carnosol reduces the formalin-induced inflammation. Furthermore, the extract and carnosol did not affect plasma corticosterone levels compared with the control group. Interestingly, both the extract and carnosol inhibited COX1 and COX2 activity. It could be concluded that ROL extract and carnosol suppressed pain and inflammation induced by formalin injection, which may be due to inhibition of COX1 and COX2 enzymes activity.
Synthesen und Strukturen neuer Komplexes des 2,2′‐Bipyridins mit Niob, Molybdän, Wolfram und Rhenium in hohen Oxidationsstufen (1990)

Syntheses and Structures of New 2,2′‐Bipyridine Complexes of Niobium, Molybdenum, Tungsten, and Rhenium in High Oxidation States Exchange of oxo for chlorine ligands by means of hexamethyl‐disiloxane provides an easy and effective synthesis of the oxo halides (bipy)M V OCl 3 (bipy = 2,2′‐bipyridine, C 10 H 8 N 2 ; M = Nb, 1c; Re, 2c; W, 3c) and (bipy)M VI O 2 Cl 2 (N = Mo, 6a ;W, 6b ). Starting from ReCl 5 the structurally (X‐ray) characterized byproduct (bipy)Re IV Cl 4 ( 2b ) is also formed. Dirhenium heptaoxide ( 7 ) is converted into the complex (bipy)Re VII O 3 Cl ( 8 ) upon treatment with chlorotrimethylsilane in the presence of 2,2′‐bipyridine, thus being now easily available a key compound in rhenium chemistry. The new imido complexes of composition (bipy)MoVI(NR) 2 Cl 2 [R = C(H 3 ) 3 , 9a ; C 6 H 5 , 9b ] are accessible from 6a and the corresponding silylated amines. The rhenium and tungsten complexes 2b and 6b , resp., exhibit octahedral structures in the crystal, with that of 6b being distorted as a result of different ligands and intermolecular contacts.
Forced Resonant Type EMI Dipole Antennas for Frequencies Below 80 MHz (2002)

This paper presents the basic characteristics of a forced resonant type EMI dipole antennas for frequencies below 80 MHz in which two reactance elements are used for the impedance matching at the feed point. The input impedance of the short dipole less than half-wavelength is controlled by the properly determined loading position and the value of loading reactance. The numerical results show that the small-sized EMI dipole antenna with lower antenna factors for frequencies below 80 MHz can be realized by the reactance loading. In case the proposed center driven forced resonant type EMI dipole antenna with 0.3λ length is loaded from the center, the input impedance is matched at feed line with 50 Ω, and hence the antenna has lower factors in the frequency range of 30 to 80 MHz.
Phase II Trial of Weekly Single-Agent Paclitaxel in Platinum/Paclitaxel-Refractory Ovarian Cancer (2002)

Weekly paclitaxel (80 mg/m(2)) is generally well tolerated and is an active second-line regimen against ovarian cancer that has demonstrated resistance to platinum/paclitaxel delivered on an every-3-week schedule.
[Mo154(NO)14O420(OH)28(H2O)70](25 ± 5)−: A Water‐Soluble Big Wheel with More than 700 Atoms and a Relative Molecular Mass of About 24000 (1995)

Complex clusters the size of small proteins can be generated in reduced molybdate solutions by linking defined fragments. An example of this is the giant cluster (NH 4 ) 25±5 [Mo 154 (NO) 14 O 420 (OH) 28 (H 2 O) 70 ]·ca. 350 H 2 O with a molar mass of more than 30000 gmol −1 , the anion of which is shaped like a tire with a nanodimensional cavity more than 20 Å in diameter and has an extremely large inner and outer surface as well as a large number of mobile electrons.
Synthesis and degradation of endothelin-1 (2003)

The endothelin-converting enzyme (ECE) is the main enzyme responsible for the genesis of the potent pressor peptide endothelin-1 (ET-1). It is suggested that the ECE is pivotal in the genesis of ET-1, considering that the knockout of both genes generates the same lethal developments during the embryonic stage. Several isoforms of the ECE have been disclosed, namely ECE-1, ECE-2, and ECE-3. Within each of the first two groups, several sub-isoforms derived through splicing of single genes have also been identified. In this review, the characteristics of each sub-isoform for ECE-1 and 2 will be discussed. It is important to mention that the ECE is, however, not the sole enzyme involved in the genesis of endothelins. Indeed, other moieties, such as chymase and matrix metalloproteinase II, have been suggested to be involved in the production of ET intermediates, such as ET-1 (1-31) and ET-1 (1-32), respectively. Other enzymes, such as the neutral endopeptidase 24-11, is curiously not only involved in the degradation and inactivation of ET-1, but is also responsible for the final production of the peptide via the hydrolysis of ET-1 (1-31). In this review, we will attempt to summarize, through the above-mentioned characteristics, the current wisdom on the role of these different enzymes in the genesis and termination of effect of the most potent pressor peptide reported to date.
All-fiber source of 100-nJ subpicosecond pulses (1994)

Chirped pulse amplification of a stretched pulse passively mode-locked erbium fiber laser is demonstrated. The two-stage all-fiber amplifier system delivers 800-fs pulses with pulse energies up to 100 nJ at a repetition rate of 200 kHz.
Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function (2018)

SUMMARY Human T cells are central effectors of immunity and cancer immunotherapy. CRISPR-based functional studies in T cells could prioritize novel targets for drug development and improve the design of genetically reprogrammed cell-based therapies. However, large-scale CRISPR screens have been challenging in primary human cells. We developed a new method, s gRNA l entiviral i nfection with C as9 protein e lectroporation (SLICE), to identify regulators of stimulation responses in primary human T cells. Genome-wide loss-of-function screens identified essential T cell receptor signaling components and genes that negatively tune proliferation following stimulation. Targeted ablation of individual candidate genes validated hits and identified perturbations that enhanced cancer cell killing. SLICE coupled with single-cell RNA-Seq revealed signature stimulation-response gene programs altered by key genetic perturbations. SLICE genome-wide screening was also adaptable to identify mediators of immunosuppression, revealing genes controlling response to adenosine signaling. The SLICE platform enables unbiased discovery and characterization of functional gene targets in primary cells.
β-D-1, 3 GLUCANASES IN FUNGI (1959)

β-D-1,3 Glucanases are of common occurrence in fungi, being detected in the culture nitrates of 96% of the organisms tested in shake flasks and in the sporophores of six basidiomycetcs. The enzyme is constitutive. Basidiomycete QM 806 and Sporotrichum pruinosum QM 826 are excellent sources of β-D-1,3 glucanase of the exo-type giving glucose as the sole reducing product of laminarin hydrolysis. Rhizopus arrhizus QM 1032 produces a β-D-1,3 glucanase of the endo-type giving laminaribiose and higher oligosaccharides as the products of hydrolysis of β-D-1,3 glucans. By controlling the conditions of growth β-D-1,3 glucanases can be produced free of β-1,4 glucanase (cellulase).
Biosynthesis of Isoprenoids: Characterization of a Functionally Active Recombinant 2-C-methyl-D-erythritol 4-phosphate Cytidyltransferase (IspD) from Mycobacterium tuberculosis H37Rv (2007)

Tuberculosis, caused by Mycobacterium tuberculosis, continues to be one of the leading infectious diseases to humans. It is urgent to discover novel drug targets for the development of antitubercular agents. The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has been considered as an attractive target for the discovery of novel antibiotics for its essentiality in bacteria and absence in mammals. MEP cytidyltransferase (IspD), the third-step enzyme of the pathway, catalyzes MEP and CTP to form 4-diphosphocytidyl-2-C-methylerythritol (CDP-ME) and PPi. In the work, ispD gene from M. tuberculosis H37Rv (MtIspD) was cloned and expressed. With N-terminal fusion of a histidine-tagged sequence, MtIspD could be purified to homogeneity by one-step nickel affinity chromatography. MtIspD exists as a homodimer with an apparent molecular mass of 52 kDa. Enzyme property analysis revealed that MtIspD has high specificity for pyrimidine bases and narrow divalent cation requirements, with maximal activity found in the presence of CTP and Mg(2+). The turnover number of MtIspD is 3.4 s(-1). The Km for MEP and CTP are 43 and 92 muM, respectively. Furthermore, MtIspD shows thermal instable above 50 degrees C. Circular dichroism spectra revealed that the alteration of tertiary conformation is closely related with sharp loss of enzyme activity at higher temperature. This study is expected to help better understand the features of IspD and provide useful information for the development of novel antibiotics to treat M. tuberculosis.
A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models (2013)

Frequent infusions of intravenous factor VIII (FVIII) are required to prevent bleeding associated with hemophilia A. To reduce the treatment burden, recombinant FVIII with a longer half-life was developed without changing the protein structure. FVIII-polyethylene glycol (PEG) conjugates were prepared using an enzymatic process coupling PEG (ranging from 10 to 80 kDa) selectively to a unique O-linked glycan in the FVIII B-domain. Binding to von Willebrand factor (VWF) was maintained for all conjugates. Upon cleavage by thrombin, the B-domain and the associated PEG were released, generating activated FVIII (FVIIIa) with the same primary structure and specific activity as native FVIIIa. In both FVIII- and VWF-deficient mice, the half-life was found to increase with the size of PEG. In vivo potency and efficacy of FVIII conjugated with a 40-kDa PEG (N8-GP) and unmodified FVIII were not different. N8-GP had a longer duration of effect in FVIII-deficient mouse models, approximately a twofold prolonged half-life in mice, rabbits, and cynomolgus monkeys; however, the prolongation was less pronounced in rats. Binding capacity of N8-GP on human monocyte-derived dendritic cells was reduced compared with unmodified FVIII, resulting in several-fold reduced cellular uptake. In conclusion, N8-GP has the potential to offer efficacious prevention and treatment of bleeds in hemophilia A at reduced dosing frequency.
Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation (2013)

The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28(-)CD57(+)), highly proliferative (Ki67(+)), oligoclonal, memory-like CD4 and CD8 T cells (CCR7(-)CD45RA(-) or CCR7(-)CD45RA(+)) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.
Alpha Beta-Hydrolase Fold Enzymes Structures, Functions and Mechanisms (2000)

The alpha/beta-hydrolase fold family of enzymes is rapidly becoming one of the largest group of structurally related enzymes with diverse catalytic functions. Members in this family include acetylcholinesterase, dienelactone hydrolase, lipase, thioesterase, serine carboxypeptidase, proline iminopeptidase, proline oligopeptidase, haloalkane dehalogenase, haloperoxidase, epoxide hydrolase, hydroxynitrile lyase and others. The enzymes all have a Nucleophile-His-Acid catalytic triad evolved to efficiently operate on substrates with different chemical composition or physicochemical properties and in various biological contexts. For example, acetylcholine esterase catalyzes the cleavage of the neurotransmitter acetylcholine, at a rate close to the limits of diffusion of substrate to the active site of the enzyme. Dienelactone hydrolase uses substrate-assisted catalysis to degrade aromatic compounds. Lipases act adsorbed at the water/lipid interface of their neutral water-insoluble ester substrates. Most lipases have their active site buried under secondary structure elements, a flap, which must change conformation to allow substrate to access the active site. Thioesterases are involved in a multitude of biochemical processes including bioluminiscence, fatty acid- and polyketide biosynthesis and metabolism. Serine carboxypeptidases recognize the negatively charged carboxylate terminus of their peptide substrates. Haloalkane dehalogenase is a detoxifying enzyme that converts halogenated aliphatics to the corresponding alcohols, while haloperoxidase catalyzes the halogenation of organic compounds. Hydroxynitrile lyase cleaves carbon-carbon bonds in cyanohydrins with concomitant hydrogen cyanide formation as a defense mechanism in plants. This paper gives an overview of catalytic activities reported for this family of enzymes by discussing selected examples. The current state of knowledge of the molecular basis for catalysis and substrate specificity is outlined. Relationships between active site anatomy, topology and conformational rearrangements in the protein molecule is discussed in the context of enzyme mechanism of action.
Catherine Millet y la nueva literatura erótica francesa (2002)

No hay resumen
Novel radiosensitizers for tumors of the central nervous system. (2004)

Radiotherapy is widely used in the management of tumors of the central nervous system (CNS) primarily because these tumors, in general, remain localized and are usually not completely removed at surgery. Therefore, radiotherapy serves as a valuable adjunct. However, due to radiation resistance, survival for most patients with CNS tumors remains poor. Radiosensitizers are considered useful for CNS tumors because the majority of these tumors cause death due to local progression, thus emphasizing the significance of improving local control. In addition, these neoplasms consist of a rapidly growing cell population surrounded by slowly proliferating normal brain cells, thereby affording an opportunity for tumor-selectivity. Historically, several classes of radiation sensitizers, including S-phase halogenated pyrimidines, oxygen mimetics and others, have been tested without clear evidence of clinical benefit. Recently, two agents with very different mechanisms of action have gained attention and are currently in clinical trials; these agents, efaproxiral, a modulator of tumor hypoxia, and motexafin-gadolinium, a redox modulator, are the focus of this review.