gebhart/patrepeval huggingface dataset:
Structure-based engineering to restore high affinity binding of an isoform-selective anti-TGFβ1 antibody (2018)

Metelimumab (CAT192) is a human IgG4 monoclonal antibody developed as a TGFβ1-specific antagonist. It was tested in clinical trials for the treatment of scleroderma but later terminated due to lack of efficacy. Subsequent characterization of CAT192 indicated that its TGFβ1 binding affinity was reduced by ∼50-fold upon conversion from the parental single-chain variable fragment (scFv) to IgG4. We hypothesized this result was due to decreased conformational flexibility of the IgG that could be altered via engineering. Therefore, we designed insertion mutants in the elbow region and screened for binding and potency. Our results indicated that increasing the elbow region linker length in each chain successfully restored the isoform-specific and high affinity binding of CAT192 to TGFβ1. The crystal structure of the high binding affinity mutant displays large conformational rearrangements of the variable domains compared to the wild-type antigen-binding fragment (Fab) and the low binding affinity mutants. Insertion of two glycines in both the heavy and light chain elbow regions provided sufficient flexibility for the variable domains to extend further apart than the wild-type Fab, and allow the CDR3s to make additional interactions not seen in the wild-type Fab structure. These interactions coupled with the dramatic conformational changes provide a possible explanation of how the scFv and elbow-engineered Fabs bind TGFβ1 with high affinity. This study demonstrates the benefits of re-examining both structure and function when converting scFv to IgG molecules, and highlights the potential of structure-based engineering to produce fully functional antibodies.
International Sensitivity Index Calibration of the Near-Patient Testing Prothrombin Time Monitor, ProTime (2003)

Near-patient testing devices (monitors) capable of measuring prothrombin time on an unmeasured drop of blood would be suitable alternatives to centralized laboratory monitoring of patients receiving oral anticoagulants. The essential prerequisite for the use of these monitors is their conformity to the international sensitivity index (ISI) calibration model recommended by the World Health Organization. We report on the ISI calibration of the ProTime monitor (International Technidyne, Edison, NJ) designed and approved for patient self-testing. According to our results, this monitor can be calibrated by adopting the model already used for other monitors. The apparent ISI was close to unity. Overall, the international normalized ratio values displayed by the monitor agreed with those measured with the international reference preparation for thromboplastin. Confirmation of these results in a large multicenter study is warranted.
Inflammation and Parkinson's disease pathogenesis (2010)

Inflammation is a neuropathological feature of parkinsonian brains and also in experimental models of the disease. It is believed that activated glial cells, which compose the majority of this inflammatory response contribute to the neurodegenerative process through the production of toxic molecules. Therapeutic strategies geared toward reducing inflammation and inhibiting the production of these glial-derived toxic molecules may be a promising neuroprotective strategy for the treatment of Parkinson's disease and related conditions.
Modeling surfaces of arbitrary topology using manifolds (1995)

Article Modeling surfaces of arbitrary topology using manifolds Share on Authors: Cindy M. Grimm The Science and Technology Center for Computer Graphics and Scientific Visualization The Science and Technology Center for Computer Graphics and Scientific VisualizationView Profile , John F. Hughes The Science and Technology Center for Computer Graphics and Scientific Visualization The Science and Technology Center for Computer Graphics and Scientific VisualizationView Profile Authors Info & Claims SIGGRAPH '95: Proceedings of the 22nd annual conference on Computer graphics and interactive techniquesSeptember 1995 Pages 359–368https://doi.org/10.1145/218380.218475Published:15 September 1995 89citation990DownloadsMetricsTotal Citations89Total Downloads990Last 12 Months18Last 6 weeks2 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my AlertsNew Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteGet Access
Electron Spin Resonance Spectroscopy of Triplet Electron Pairs in Diacetylene Crystals (1987)

Recent ESR spectra of linear chain diacetylene oligomer and polymer systems are described. The electronic properties of the polymer and of the intermediates are deduced from the triplet radical pair character of their ground and excited states. It will be demonstrated that the polydiacetylenes represent a unique model system for the study of the pz-electron system in conjugated polymers. There is a strong correlation between the pz-electron structure of the intermediate states and that of the polaron and bipolaron states. The ground state of the radical electron pairs is a singlet state with S = 0. The excited states are given by triplets (S = 1) and quintets (S = 2) as well as by mixed singlet-quintet states. Recent time resolved ESR spectra of the polymer are interpreted to be due to S = 1 bipolaron states.
Apparent modulation of CD20 by rituximab: an alternative explanation (2004)

We read with interest the paper from Jilani et al[1][1] in which rituximab treatment appeared to down-modulate CD20 expression through a combination of internalization and RNA regulation. The result is unexpected because previous studies had shown that CD20 is not modulated by monoclonal antibody (
Mutations that alter ligand-induced switches and dimerization activities in the retinoid X receptor. (1994)

The retinoid X receptor (RXR) heterodimerizes with a variety of nuclear receptors. In addition, RXR forms homodimers in the presence of its ligand, 9-cis-retinoic acid. From deletion and point mutation analysis we present evidence that a short region (amino acids 413 to 443) in the carboxy terminus of RXR alpha is critical for both homo- and heterodimeric interactions as well as for diverse functional activities. In addition, we present evidence that homo- and heterodimer functions can be separated. The deletion of 19 amino acids from the C-terminal end of RXR dramatically reduced the transcriptional activation function of RXR. The removal of 10 additional amino acids resulted in a receptor (delta RXR3) that had completely lost its ligand-dependent homodimer function but retained its heterodimer activities. Heterodimer function was abolished by the deletion of an additional 20 amino acids. Single amino acid substitutions in the region generated receptors with altered RXR homodimer DNA binding, while simultaneous mutation of three Leu residues (Leu-418, -419 and -422) completely abolished both RXR homodimer and heterodimer DNA binding activities. Mutation of Leu-430 to Phe (L430-F) resulted in a receptor that bound to DNA strongly as homodimers in a ligand-independent manner, while another single amino acid exchange (L422-Q) led to a mutant that behaved in a manner exactly opposite to that of wild-type RXR in that the homodimerization of the mutant occurred in the absence of ligand and was inhibited by 9-cis-retinoic acid. In transfection assays, both L422-Q and L430-F failed to act as homodimers but retained their heterodimer function. Our studies demonstrate the unique properties of the RXR ligand binding domain and point to specific residues that mediate homo- and heterodimer activities and ligand-induced conformational switches.
Qualitative Analysis of Immune Function in Patients with the Acquired Immunodeficiency Syndrome (1985)

We studied purified subpopulations of lymphocytes from patients with the acquired immunodeficiency syndrome (AIDS) in order to determine whether intrinsic defects in lymphocyte function, aside from those due to alterations in lymphocyte numbers, were present. Mitogen-stimulated DNA synthesis, production of gamma interferon, production of interleukin-2, and expression of interleukin-2 receptors, although variably decreased in unseparated cell populations, were normal in populations of purified T-cell subsets. In contrast, DNA synthesis in response to the soluble protein antigen tetanus toxoid was decreased in both unseparated and purified T-cell subpopulations. Cell-mixing experiments demonstrated that the hyporesponsiveness of the unfractionated lymphocytes from patients with AIDS was not due to active suppression. We conclude that the lymphocytes of patients with AIDS, although capable of undergoing a normal degree of blast transformation and lymphokine production after mitogenic stimulation, have an intrinsic defect in their ability to recognize and respond to soluble antigen.
Catalytic oxidation of alk-1-enes to aldehydes (1986)

B. L. Feringa, J. Chem. Soc., Chem. Commun., 1986, 909 DOI: 10.1039/C39860000909
Neuronal Diversity and Temporal Dynamics: The Unity of Hippocampal Circuit Operations (2008)

In the cerebral cortex, diverse types of neurons form intricate circuits and cooperate in time for the processing and storage of information. Recent advances reveal a spatiotemporal division of labor in cortical circuits, as exemplified in the CA1 hippocampal area. In particular, distinct GABAergic (gamma-aminobutyric acid-releasing) cell types subdivide the surface of pyramidal cells and act in discrete time windows, either on the same or on different subcellular compartments. They also interact with glutamatergic pyramidal cell inputs in a domain-specific manner and support synaptic temporal dynamics, network oscillations, selection of cell assemblies, and the implementation of brain states. The spatiotemporal specializations in cortical circuits reveal that cellular diversity and temporal dynamics coemerged during evolution, providing a basis for cognitive behavior.
Dual catalysis for enantioselective convergent synthesis of enantiopure vicinal amino alcohols (2018)

Enantiopure vicinal amino alcohols and derivatives are essential structural motifs in natural products and pharmaceutically active molecules, and serve as main chiral sources in asymmetric synthesis. Currently known asymmetric catalytic protocols for this class of compounds are still rare and often suffer from limited scope of substrates, relatively low regio- or stereoselectivities, thus prompting the development of more effective methodologies. Herein we report a dual catalytic strategy for the convergent enantioselective synthesis of vicinal amino alcohols. The method features a radical-type Zimmerman-Traxler transition state formed from a rare earth metal with a nitrone and an aromatic ketyl radical in the presence of chiral N,N'-dioxide ligands. In addition to high level of enantio- and diastereoselectivities, our synthetic protocol affords advantages of simple operation, mild conditions, high-yielding, and a broad scope of substrates. Furthermore, this protocol has been successfully applied to the concise synthesis of pharmaceutically valuable compounds (e.g., ephedrine and selegiline).
MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system (2007)

The data we present facilitate prediction of likely modes of miRNA function in the CNS and many miRNA expression profiles are consistent with the mutual exclusion mode of function in which there is spatial or temporal exclusion of miRNAs and their targets. However, some miRNAs, such as those with cell-type specific expression, are more likely to be co-expressed with their targets. Our data provide an important resource for future functional studies of miRNAs in the CNS.
New EMBO Member's Review Defective downregulation of receptor tyrosine kinases in cancer (2004)

Most growth factors control cellular functions by activat-ing speciﬁc receptor tyrosine kinases (RTKs). While over-activation of RTK signalling pathways is stronglyassociated with carcinogenesis, it is becoming increas-ingly clear that impaired deactivation of RTKs may alsobe a mechanism in cancer. A major deactivation pathway,receptor downregulation, involves ligand-induced endocy-tosis of the RTK and subsequent degradation in lysosomes.A complex molecular machinery that uses the small pro-tein ubiquitin as a key regulator assures proper endocy-tosis and degradation of RTKs. Here we discuss evidencethat implicates deregulation of this machinery in cancer.The EMBO Journal (2004) 23, 2707–2712. doi:10.1038/sj.emboj.7600292; Published online 1 July 2004Subject Categories: membranes & transport; molecularbiology of diseaseKeywords: Cbl; endocytosis; signal transduction; Tsg101;ubiquitin
Elastase-induced experimental aneurysms in rats. (1990)

An experimental in vivo model of aortic aneurysm was established by perfusing an isolated segment of rat abdominal aorta with pancreatic elastase. Ten rats were used in each protocol. Saline-perfused aortas developed no aneurysmal dilations. Elastase-perfused aortas contained aneurysms in the perfused area and a total loss of elastic tissue. Control aortas contained no elastic tissue lesions. There was a quantitative relation between the amount of elastase perfused and aneurysm formation: 1-2 units induced neither macroscopic nor microscopic lesions; 3-6 units induced microscopic elastic tissue damage without macroscopic aneurysm; and more than 6 units produced aneurysmal dilation in all cases. In situ elastase secretion by macrophages was induced by perfusing rat aortas with thioglycollate-activated macrophages or with thioglycollate alone. There was aortitis without true aneurysm and a total loss of elastic tissue in the vicinity of activated macrophages within the aortic media. Perfusion of infra-aneurysmal amount of elastase (1 or 2 units) or thioglycollate plus plasmin (2 units) always induced a large aneurysm, whereas plasmin alone induced neither macroscopic nor microscopic lesions. These morphological results were supported by the significantly elevated elastolytic activity within the aortic wall of animals perfused with thioglycollate plus plasmin 9 days, after perfusion (207.6 +/- 54.8 micrograms elastin-rhodamine lysed/18 hr; control rats, 25.43 +/- 11.13). The results suggest that the presence of elastase within the aortic media leads to aneurysm formation. Activated macrophages within the aortic media may be responsible for elastase secretion and elastic tissue destruction. Plasmin may enhance elastase activity and aggravate the aneurysmal lesion.
Cyclin A2:At the crossroads of cell cycle and cell invasion (2015)

Cyclin A2 is an essential regulator of the cell division cycle through the activation of kinases that participate to the regulation of S phase as well as the mitotic entry. However,whereas its degradation by the proteasome in mid mitosis was thought to be essential for mitosis to proceed,recent observations show that a small fraction of cyclin A2 persists beyond metaphase and is degraded by autophagy. Its implication in the control of cytoskeletal dynamics and cell movement has unveiled its role in the modulation of Rho A activity. Since this GTPase is involved in both cell rounding early in mitosis and later,in the formation of the cleavage furrow,this suggests that cyclin A2 is a novel actor in cytokinesis. Taken together,these data point to this cyclin as a potential mediator of cell-niche interactions whose dysregulation could be taken as a hallmark of metastasis.
Adenoviruses from Human Immunodeficiency Virus-Infected Individuals, Including Two Strains That Represent New Candidate Serotypes Ad50 and Ad51 of Species B1 and D, Respectively (1999)

Adenovirus (Ad) isolates from a large number of human immunodeficiency virus (HIV)-infected individuals were compared serologically and genetically with Ad isolates from immunocompetent patients. Between 1982 and 1994, stool and urine samples from 137 subjects with AIDS hospitalized in The Netherlands yielded 143 Ad strains. Forty additional Ad strains were obtained from 35 HIV-positive patients in Manchester, United Kingdom, in 1992 and 1993. Of these 183 HIV-associated Ad strains, 84% belonged to species D and 3% belonged to species C. These strains were compared with 2,301 Ad strains collected during general diagnostic examinations in The Netherlands from 1973 to 1992. Of the latter strains, 5% belonged to species D and 49% belonged to species C. Two of the Ads isolated from fecal specimens of AIDS patients represent new serotypes: candidate Ad serotype 50 (prototype strain, Wan) of subspecies B1 and candidate Ad serotype 51 (prototype strain, Bom) of species D. The DNA restriction enzyme patterns of strains Wan and Bom differed from the patterns of all established prototypes.
Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2000 British Association for Psychopharmacology guidelines (2008)

A revision of the 2000 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in May 2006. Key areas in treating depression were reviewed, and the strength of evidence and clinical implications were considered. The guidelines were drawn up after extensive feedback from participants and interested parties. A literature review is provided, which identifies the quality of evidence to inform the recommendations, the strength of which are based on the level of evidence. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse, and stopping treatment.
Immunoglobulin κ gene expression after stable integration (1989)

MOPC41 immunoglobulin kappa gene constructs have been stably introduced into the mouse germ line to investigate the effects of deleting the conserved intronic sequences on gene expression. Intact kappa genes containing 1.5 kilobase pairs of upstream and 8.5 kilobase pairs of downstream flanking sequences were highly expressed tissue-specifically, raising the total level of kappa mRNA in spleens severalfold in most transgenic animals. This high expression was often accompanied by marked suppression of endogenous kappa gene activity. Transgenes containing a deletion of the matrix association region (MAR) or both the MAR and enhancer were expressed tissue-specifically at mean levels only 2- and 3-fold lower, respectively, than that of intact transgenes. Therefore, while the intronic enhancer and MAR appear to play a quantitative role in gene expression, these sequences are not absolutely essential for transcriptional activation of rearranged kappa genes in a normal developmental environment.
Production of Antibodies Against Phosphocholine, Phosphatidylcholine, Sphingomyelin, and Lipid A by Injection of Liposomes Containing Lipid A (1979)

Abstract Liposomes were investigated as a combined carrier and adjuvant to promote the immunogenicity of lipid A derived from endotoxin. Lipid A-containing liposomes, or lipid A alone, were injected once into rabbits either subcutaneously or i.v. Antiserum activity was measured by complement-dependent damage to appropriate indicator liposomes containing trapped glucose. Lipid A in liposomes produced a greater immune response against lipid A than that obtained by injecting identical amounts of lipid A alone, and the response to the liposome-lipid A combination was equivalent to that obtained by a frequently used alternative method, in which the antigen consisted of acid-treated bacterial cells coated with lipid A. Antiserum, or purified IgG antibodies, from rabbits immunized with liposomes containing lipid A also reacted with liposomes lacking lipid A. The antibodies were inhibited by phosphocholine, and the activity was adsorbed by phosphatidylcholine, or ceramide phosphocholine (sphingomyelin). The anti-phosphocholine antibodies did not cross-react with lipid A, but their binding to liposomes was inhibited by the presence of anti-lipid A antibodies on the surface of the liposomes. An “anti-liposome” response was not observed when either lipid A alone, acid-treated bacterial cells coated with lipid A, or liposomes lacking lipid A were injected. We conclude that one injection of liposomes containing lipid A produces an immune response against lipid A that is equivalent to that produced by other methods of immunization. Injection of liposomes containing lipid A also produces an immune response against phosphocholine, phosphatidylcholine, and sphingomyelin.
Vesicular fractions of sunflower apoplastic fluids are associated with potential exosome marker proteins (2009)

Based on the presence of phospholipids in the extracellular fluids (EFs) of sunflower seeds, we have hypothesized on the existence of vesicles in the apoplastic compartment of plants. Ultracentrifugation of sunflower EF allowed the isolation of particles of 50-200 nm with apparent membrane organization. A small GTPase Rab was putatively identified in this vesicular fraction. Since Rab proteins are involved in vesicular traffic and their presence in exosomes from animal fluids has been demonstrated, evidence presented here supports the existence of exosome-like vesicles in apoplastic fluids of sunflower. Their putative contribution to intercellular communication in plants is discussed.
Perioperative Coagulation Management and Control of Platelet Transfusion by Point-of-Care Platelet Function Analysis (2007)

About one third of all blood components transfused intraoperatively is used in cardiac surgery, whereas mortality of cardiosurgical patients correlates nearly linear with the number of transfused units of packed red blood cells. Acquired platelet function disorders play a major role in perioperative bleeding in cardiac surgery. Therefore, the use of point-of-care-suitable platelet function analyzers seems to be reasonable in this field. Methods: Platelet function analyzer PFA-100®, rotational thrombelastometry (ROTEM®), and multiple platelet function analyzer (Multiplate®) are in principle applicable for point-of-care testing. Since these three analyzers monitor different aspects of platelet function and have different limitations, the selection of the right test system depends on the right question. Results: Perioperative use of platelet function analyzers is helpful in prediction of blood loss in cardiac surgery. Perioperative usage of blood components and their respective costs can be reduced by an appropriate coagulation management. Conclusion: Algorithms for perioperative coagulation management based on point-of-care testing permit a fast diagnostic and goal-directed therapy of coagulation and functional platelet disorders. The possibility to reduce the mortality of patients and the overall cost for hospital stay is subject of further studies.