gebhart/patrepeval huggingface dataset:
Acetylcholine beyond neurons: the non‐neuronal cholinergic system in humans (2008)

Animal life is controlled by neurons and in this setting cholinergic neurons play an important role. Cholinergic neurons release ACh, which via nicotinic and muscarinic receptors (n- and mAChRs) mediate chemical neurotransmission, a highly integrative process. Thus, the organism responds to external and internal stimuli to maintain and optimize survival and mood. Blockade of cholinergic neurotransmission is followed by immediate death. However, cholinergic communication has been established from the beginning of life in primitive organisms such as bacteria, algae, protozoa, sponge and primitive plants and fungi, irrespective of neurons. Tubocurarine- and atropine-sensitive effects are observed in plants indicating functional significance. All components of the cholinergic system (ChAT, ACh, n- and mAChRs, high-affinity choline uptake, esterase) have been demonstrated in mammalian non-neuronal cells, including those of humans. Embryonic stem cells (mice), epithelial, endothelial and immune cells synthesize ACh, which via differently expressed patterns of n- and mAChRs modulates cell activities to respond to internal or external stimuli. This helps to maintain and optimize cell function, such as proliferation, differentiation, formation of a physical barrier, migration, and ion and water movements. Blockade of n- and mACHRs on non-innervated cells causes cellular dysfunction and/or cell death. Thus, cholinergic signalling in non-neuronal cells is comparable to cholinergic neurotransmission. Dysfunction of the non-neuronal cholinergic system is involved in the pathogenesis of diseases. Alterations have been detected in inflammatory processes and a pathobiologic role of non-neuronal ACh in different diseases is discussed. The present article reviews recent findings about the non-neuronal cholinergic system in humans.
Mechanism and Theory in Organic Chemistry (1976)

1. The Covalent Bond. 2. Some Fundamentals of Physical Organic Chemistry. 3. Acids and Bases. 4. Aliphatic Nucleophilic Substitution. 5. Intramolecular Cationic Rearrangements. 6. Carbanions, Carbenes, and Electrophilic Aliphatic Substitution. 7. Addition and Elimination Reactions. 8. Reactions of Carbonyl Compounds. 9. Radical Reactions. 10. The Theory of Pericyclic Reactions. 11. Applications of the Pericyclic Selection Rules. 12. Photochemistry. Answer Book.
Enzymatic Resolution of Aminocyclopentenols as Precursors to d- and l-Carbocyclic Nucleosides (1998)

Racemic cis-4-aminocyclopent-2-en-1-ols were synthesized in three steps utilizing hetero Diels−Alder chemistry. Starting from suitably protected hydroxylamines, oxidization with sodium periodate and trapping with cyclopentadiene afforded cycloadducts (±)-5a−d. The N−O bond of the cycloadducts was reduced with Mo(CO)6 to afford (±)-cis-4-aminocyclopent-2-en-1-ols (±)-6a−d. These compounds, or their corresponding acetates, were kinetically resolved by enzymatic acetylation or hydrolysis, respectively. Enzymatic acetylation of cis-N-(benzylcarbamoyl)-4-aminocyclopent-2-enol [(±)-6a] with Candida antarctica B lipase and Pseudomonas species lipase gave the corresponding acetate (−)-7a in 90% and 92% ee, respectively, after 40% conversion. Enzymatic hydrolysis of cis-N-acetyl-4-aminocyclopent-2-enol 1-O-acetate (±)-7d with electric eel acetylcholine esterase was successful in providing both cis-N-acetyl-4-aminocyclopent-2-enols (+)-6d and (+)-7d in 92% ee (99% ee after a single recrystallization) after 40% conversion. Further synthetic transformations of these resolved synthetic building blocks and derivatives are also reported.
European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma (2014)

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).
Desaminierungsreaktionen, 44. Zerfall von 1‐Alkylcyclopropandiazonium‐Ionen (1986)

Abstract 1‐Methyl‐ ( 17 ), 1,2‐Dimethyl‐ ( 41, 44 ), 1‐Propyl‐ ( 64 ), 1‐(1‐Methylethyl)cyclopropandiazonium‐Ionen ( 80 ) und [1,1′‐Bicyclopropyl]‐1‐diazonium‐Ionen ( 93 ) wurden durch alkalische Spaltung der entsprechenden Nitrosocarbamate in Methanol erzeugt. Cyclopropyl‐Allyl‐Umlagerung und nucleophile Substitution sind die alleinigen Reaktionen von 17 , 41 , 44 und 93 , während bei 64 und 80 Eliminierung und 1,2‐Verschiebung eines α‐Wasserstoffs zunehmend konkurrieren. Die Stereochemie von Ringöffnung und nucleophiler Substitution wurde untersucht, im Fall von 17 und 93 mit Hilfe von 2‐D‐Markierung. Cyclopropandiazonium‐Ionen ( 1 ) und 41 reagieren stereospezifisch, 17 und 44 stereoselektiv (ca. 85:15) und 93 völlig unselektiv. Die Ergebnisse sprechen für einen allmählichen Übergang von konzertierten zu schrittweisen Reaktionsabläufen. Um das S N 1‐Extrem zu erreichen, ist eine erhebliche Stabilisierung der positiven Ladung erforderlich.
The development of dioptric projection lenses for DUV lithography (2002)

Advanced dioptric projection lenses from Carl Zeiss are used in some of the world's most advanced deep ultraviolet projection lithography systems. These lenses provide a resolution of better than 100 nm across the entire field of view with a level of aberration control that maximizes critical dimension uniformity and lithographic process latitude. These dioptric projection lenses are currently being used for critical layer device patterning for a wide array of complex logic, memory, and application specific integrated circuits. Zeiss' involvement in the develop of ultraviolet lenses goes back to the year 1902, exactly 100 years ago, when Moritz von Rohr calculated the first monochromatic ultraviolet micro-objectives for ultra-high resolution microphotography using a line-narrowed source. The modern dioptric projection lenses for lithography are influenced by the collective experience in the field of microscopy, and the more recent experience with early step-and-repeat lenses. This paper discusses some of the foundations of modern dioptric designs in the context of this history, demonstrating that rapid synthesis of designs is possbile using combinations of monochromatic microscope objectives and early step-and-repeat lenses from the 1970's. The problems associated with ultra high numerical aperture objectives are discussed. Specifically, it is demonstrated that aspheres can be used effective to reduce the volume of full field projection lenses, making the mechanical implementation of a 0.90 NA lens feasible in production. Several contemporary dioptric projection lens designs are reviewed in detail. The extension of these designs to numerical apertures greater than 1.0 using immersion techniques is demonstrated. These immersion lenses give the potential for 40 nm resolution.
Overproduction of Penicillin-Binding Protein 7 Suppresses Thermosensitive Growth Defect at Low Osmolarity due to an spr Mutation of Escherichia coli (1996)

Escherichia coli delta prc mutants lacking periplasmic protease Prc, which was originally found involved in the C-terminal processing of penicillin-binding protein (PBP) 3, show thermosensitive growth at low osmolarity. We isolated thermoresistant revertants containing extragenic suppressor (spr) mutations. In the prc+ background the mutations also caused thermosensitivity at low osmolarity. They were all mapped at about 48 min on the chromosome and most probably allelic to one another. From this chromosomal region we cloned a gene that could correct the thermosensitive defect of an spr mutant, which turned out to be a multicopy suppressor of spr. Analysis of the nucleotide sequence predicted that the gene would code for a low-molecular-weight PBP, and penicillin-binding experiments revealed the product to be PBP 7. Disruption of the gene on the chromosome caused no apparent growth defect. PBP 7 seemed to be degraded by protease Prc. Overproduction of mutant PBP 7 that had the active site serine residue replaced with alanine did not correct the spr thermosensitivity, suggesting importance of the DD-endopeptidase activity in the multicopy suppression.
Protein Glycosylation, Conserved from Yeast to Man: A Model Organism Helps Elucidate Congenital Human Diseases (2006)

Proteins can be modified by a large variety of covalently linked saccharides. The present review concentrates on two types, protein N-glycosylation and protein O-mannosylation, which, with only a few exceptions, are evolutionary conserved from yeast to man. They are also distinguished by some special features: The corresponding glycosylation processes start in the endoplasmatic reticulum, are continued in the Golgi apparatus, and require dolichol-activated precursors for the initial biosynthetic steps. With respect to the molecular biology of both types of protein glycosylation, the pathways and the genetic background of the reactions have most successfully been studied with the genetically easy-to-handle baker's yeast, Saccharomyces cerevisae. Many of the severe developmental disturbances in children are related to protein glycosylation, for example, the CDG syndrome (congenital disorders of glycosylation) as well as congenital muscular dystrophies with neuronal-cell-migration defects have been elucidated with the help of yeast.
The urokinase‐type‐plasminogen‐activator receptor (CD87) is a pleiotropic molecule (1998)

Since its discovery over a decade ago, evidence has accumulated implicating the cell-surface urokinase receptor (u-PAR), in numerous biological processes. Most notable has been the identification of a critical role for u-PAR in the regulation of cell-surface plasminogen activation in physiological and pathological conditions. Recent evidence suggests that u-PAR, a glycosylphosphatidylinositol-linked receptor, lacking transmembrane and cytoplasmic domains, is also involved in processes not related to plasminogen activation, including cellular adhesion and the transmission of extracellular signals across the plasma membrane. Involvement of activated u-PAR in these events identifies previously unsuspected roles for this molecule and defines a new field of research in u-PAR biology. We discuss the molecular biology of u-PAR together with the underlying mechanisms responsible for the novel functional roles recently ascribed to this pleiotropic molecule.
Fluorescence correlation spectroscopy. I. Conceptual basis and theory (1974)

Abstract We describe a method for determining chemical kinetic constants and diffusion coefficients by measuring the rates of decay of spontaneous concentration fluctuations. The equilibrium of the system is not disturbed during the measurement. We measure the number of molecules of a specified type in a defined open volume as a function of time and compute the time course of the deviations from the thermodynamic mean concentration. The method is based on the principle that the rates of decay of spontaneous microscopic fluctuations are determined by the same phenomenological rate coefficients as those of macroscopic departures from equilibrium which result from external perturbations. Hence, an analysis of fluctuations yields the same chemical rate constants and diffusion coefficients as are measured by conventional procedures. In practice the number of the specified molecules is measured by a property such as absorbance or fluorescence which is specific and sensitive to chemical change. The sample volume is defined by a light beam which traverses the cell. As the molecules appear in or disappear from the light beam, either due to diffusion or chemical reaction, their concentration fluctuations give rise to corresponding fluctuations of the intensity of absorbed or emitted light. This paper presents the theory needed to derive chemical rate constants and diffusion coefficients from these fluctuations in light intensity. The theory is applied to three examples of general interest: pure diffusion in the absence of chemical reaction; the binding of a small rapidly diffusing ligand to a larger slowly diffusing macromolecule; and a unimolecular isomerization. The method should be especially useful in studying highly cooperative systems, relatively noncooperative systems with intermediate states closely spaced in free energy, small systems, and systems not readily subject to perturbations of state.
A study of Gm allotypes and immunoglobulin heavy gamma IGHG genes in Berbers, Arabs and sub‐Saharan Africans from Jerba Island, Tunisia (2001)

The Gm polymorphism of human IgG immunoglobulins was investigated in three different ethnic groups--Arabs, Berbers and 'dark-skinned people'--on Jerba Island, Tunisia. The genetic relationships among these groups and several populations from North Africa, sub-Saharan Africa, west Asia and Europe were analysed by principal coordinate analysis, Fst significance testing, and analysis of molecular variance based on haplotype frequencies. The results revealed a non-significant genetic differentiation between Arabs and Berbers from Jerba. However, the Jerbian population of sub-Saharan African origin was close to Ethiopians. Gene flow among the three Jerbian populations, as well as an East African origin of the dark-skinned individuals, is proposed to account for the observed genetic pattern. However, the genetic diversity observed among the different Tunisian populations did not show any significant correlation with either geographic or linguistic differentiation. A preliminary analysis of the restriction fragment length polymorphism of the IGHG genes in Arabs and Berbers from Jerba confirmed the close genetic relationship between the two populations. However, it also indicated a lower level of genetic diversity in the Berbers, which may be explained by more rapid genetic drift due to longer isolation on the island.
HER2 as a target for breast cancer therapy (2010)

The benefit of anti-HER2 therapies demonstrated in clinical trials indicates that HER2 is, to date, one of the most promising molecules for targeted therapy. Nevertheless, since tumor cells utilizing alternative growth signaling pathways through transmembrane receptors as well as intracellular signaling transduction molecules can bypass HER2 blockade, a future ambitious aim is the successful combination of anti-HER2 strategies with drugs directed to molecules that contribute to anti-HER2 resistance.
Effects of hypoxia and cytidine (5') diphosphocholine on the concentrations of dopamine, norepinephrine and metabolites in rat hypothalamus and striatum. (1987)

Experiments were performed in order to determine whether exogenous cytidine (5') diphosphocholine (CDP-choline) opposes the effects of an acute hypobaric hypoxia on the metabolism of catecholamines in rat striatum and hypothalamus. Hypoxia decreased striatal HVA, DOPAC, 3 MT, hypothalamic norepinephrine (NE), and increased both striatal and hypothalamic dopamine (DA). CDP-choline (1000 mg X kg-1 p.o.; 1 or 3 days) was devoid of effects in normoxia, but partially reversed 3 MT, NE and DA changes, potentiated the HVA and DOPAC decrease in hypoxic rats. Our results suggest that hypoxia could impair neurotransmitter release and that treatment with CDP-choline (acute, and especially subacute administration) opposes this impairment.
Shaping multidimensional signal spaces. I. Optimum shaping, shell mapping (1993)

The structure of the regions which provide the optimum tradeoff between gamma /sub s/ (shaping gain) and CER (constellation-expansion ratio) and between gamma /sub s/ and PAR (peak to average power ratio) in a finite dimensional space is introduced. Analytical expressions are derived for the corresponding tradeoff curves. In general, the initial parts of the curves have a steep slope. This means that an appreciable portion of the maximum shaping gain, corresponding to a spherical region, can be achieved with a small value of CER/sub s/, PAR. The technique of shell mapping is introduced. This is a change of variable which maps the optimum shaping region to a hypercube truncated within a simplex. This mapping is a useful tool in computing the performance, and also in facilitating the addressing of the optimum shaping region. Using the shell mapping, a practical addressing scheme is presented that achieves a point on the optimum tradeoff curves. For dimensionalities around 12, the point achieved is located near the knee of the corresponding tradeoff curve. For larger dimensionalities, a general shaping region with two degrees of freedom is used. This region provides more flexibility in selecting the tradeoff point.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Thematic Review Series: Glycerolipids. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes (2007)

In this article, the formation of prokaryotic and eukaryotic cardiolipin is reviewed in light of its biological function. I begin with a detailed account of the structure of cardiolipin, its stereochemistry, and the resulting physical properties, and I present structural analogs of cardiolipin that occur in some organisms. Then I continue to discuss i) the de novo formation of cardiolipin, ii) its acyl remodeling, iii) the assembly of cardiolipin into biological membranes, and iv) the degradation of cardiolipin, which may be involved in apoptosis and mitochondrial fusion. Thus, this article covers the entire metabolic cycle of this unique phospholipid. It is shown that mitochondria produce cardiolipin species with a high degree of structural uniformity and molecular symmetry, among which there is often a dominant form with four identical acyl chains. The subsequent assembly of cardiolipin into functional membranes is largely unknown, but the analysis of crystal structures of membrane proteins has revealed a first glimpse into the underlying principles of cardiolipin-protein interactions. Disturbances of cardiolipin metabolism are crucial in the pathophysiology of human Barth syndrome and perhaps also play a role in diabetes and ischemic heart disease.
Identification of BZR1-interacting Proteins as Potential Components of the Brassinosteroid Signaling Pathway in Arabidopsis Through Tandem Affinity Purification (2013)

Brassinosteroids (BRs) are essential phytohormones for plant growth and development. BRs are perceived by the cell surface receptor kinase BRI1, and downstream signal transduction through multiple components leads to activation of the transcription factors BZR1 and BZR2/BES1. BZR1 activity is highly controlled by BR through reversible phosphorylation, protein degradation, and nucleocytoplasmic shuttling. To further understand the molecular function of BZR1, we performed tandem affinity purification of the BZR1 complex and identified BZR1-associated proteins using mass spectrometry. These BZR1-associated proteins included several known BR signaling components, such as BIN2, BSK1, 14-3-3λ, and PP2A, as well as a large number of proteins with previously unknown functions in BR signal transduction, including the kinases MKK5 and MAPK4, histone deacetylase 19, cysteine proteinase inhibitor 6, a DEAD-box RNA helicase, cysteine endopeptidases RD21A and RD21B, calmodulin-binding transcription activator 5, ubiquitin protease 12, cyclophilin 59, and phospholipid-binding protein synaptotagmin A. Their interactions with BZR1 were confirmed by in vivo and in vitro assays. Furthermore, MKK5 was found to phosphorylate BZR1 in vitro. This study demonstrates an effective method for purifying proteins associated with low-abundance transcription factors, and identifies new BZR1-interacting proteins with potentially important roles in BR response.
In Vivo Induction of a High-Avidity, High-Frequency Cytotoxic T-Lymphocyte Response Is Associated with Antiviral Protective Immunity (2000)

Many approaches are currently being developed to deliver exogenous antigen into the major histocompatibility complex class I-restricted antigen pathway, leading to in vivo priming of CD8(+) cytotoxic T cells. One attractive possibility consists of targeting the antigen to phagocytic or macropinocytic antigen-presenting cells. In this study, we demonstrate that strong CD8(+) class I-restricted cytotoxic responses are induced upon intraperitoneal immunization of mice with different peptides, characterized as CD8(+) T-cell epitopes, bound to 1-microm synthetic latex microspheres and injected in the absence of adjuvant. The cytotoxic response induced against a lymphocytic choriomeningitis virus (LCMV) peptide linked to these microspheres was compared to the cytotoxic T-lymphocyte (CTL) response obtained upon immunization with the nonreplicative porcine parvovirus-like particles (PPV:VLP) carrying the same peptide (PPV:VLP-LCMV) previously described (C. Sedlik, M. F. Saron, J. Sarraseca, I. Casal, and C. Leclerc, Proc. Natl. Acad. Sci. USA 94:7503-7508, 1997). We show that the induction of specific CTL activity by peptides bound to microspheres requires CD4(+) T-cell help in contrast to the CTL response obtained with the peptide delivered by viral pseudoparticles. Furthermore, PPV:VLP are 100-fold more efficient than microspheres in generating a strong CTL response characterized by a high frequency of specific T cells of high avidity. Moreover, PPV:VLP-LCMV are able to protect mice against a lethal LCMV challenge whereas microspheres carrying the LCMV epitope fail to confer such protection. This study demonstrates the crucial involvement of the frequency and avidity of CTLs in conferring antiviral protective immunity and highlights the importance of considering these parameters when developing new vaccine strategies.