gebhart/patrepeval huggingface dataset:
Crystal structure of a complete ternary complex of T-cell receptor, peptide–MHC, and CD4 (2012)

Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted ∼65° relative to the T-cell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3εγ and CD3εδ subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T-cell selection.
New insights into the structural basis of integrin activation (2003)

Integrins are cell adhesion receptors that communicate biochemical and mechanical signals in a bidirectional manner across the plasma membrane and thus influence most cellular functions. Intracellular signals switch integrins into a ligand-competent state as a result of elicited conformational changes in the integrin ectodomain. Binding of extracellular ligands induces, in turn, structural changes that convey distinct signals to the cell interior. The structural basis of this bidirectional signaling has been the focus of intensive study for the past 3 decades. In this perspective, we develop a new hypothesis for integrin activation based on recent crystallographic, electron microscopic, and biochemical studies.
Update on emerging drugs for cancer cachexia (2009)

There are several existing and emerging drugs with the potential to ameliorate cancer cachexia, but the most efficacious treatment will probably come from combined drug therapies.
Initiation of DNA Synthesis in Escherichia Coli (1979)

PERSPECfIVES AND SUMMARY 999 DNA SYNTHESIS ON SINGLE-STRANDED CIRCULAR DNA 1001 Priming by RNA Polymerase 1002 Priming by dnaG Protein 1003 Priming by dnaG Protein in Conjunction with Other Proteins 1005 DNA SYNTHESIS ON DOUBLE-STRANDED DNA 1007 DNA Synthesis from a 3'-hydroxyl End at a Strand Break 1007 Processing of Primer RNA and Use of Two Initiation Mechanisms 1010 Activation of the Origin by Transcription 1013 Formation of Nascent Fragments 1017 INITIATION OF REPLICATION OF THE E. COLI CHROMOSOME 1020 Function of Required Gene Products 1020 Detection of the Origin of Replication 1023 REGULATION OF DNA REPLICATION ... 1026 CONCLUSIONS
Reversible Silicon Wafer Bonding for Surface Protection: Water‐Enhanced Debonding (1992)

Water can significantly enhance the equilibrium crack length generated by a blade inserted between two bonded wafers due to a decrease in the silicon surface energy in contact with water. A debonding arrangement in which only one wafer can elastically bend around the inserted blade can further increase the crack length by 19%. The suggested debonding technique is compatible with IC processing and allows to easily separate bonded silicon wafers up to 8 in. in diameter.
Polysialic acids : a tool for the optimisation of peptide and protein therapeutics. (2004)

Colominic acid (CA) is a low molecular weight derivative of polysialic acid (PSA), which is a naturally occurring biodegradable, highly hydrophilic polymer of N-acetylneuraminic acid. CA was proposed as an alternative to non-biodegradable mPEG for the delivery of proteins with short plasma half-lives, poor stability and high immunogenicity, thus facilitating their therapeutic potential. Here we add to the repertoire of proteins modified and introduce three 'new' smaller therapeutic peptides for polysialylation with a view to improving their in vitro stability, biological potency and in vivo pharmacokinetic properties. The biotherapeutics employed included, bovine polyclonal IgG and monoclonal IgG2a antibodies, which were chosen to model therapeutic Mabs which have the potential in treating cancers, autoimmune diseases and infections. The serine protease inhibitor, aprotinin chosen for the potential treatment of pancreatitis and haematological problems, insulin for treating diabetes and somatostatin (SS) for the treatment of growth disorders i.e. acromegaly. In addition, a novel strategy was developed in an attempt to further improve the efficiency and therapeutic value of the established method of polysialylation. Periodate oxidised CA was first coupled via Schiff base reductive amination to IgG (4.43%), aprotinin (29.20%), and insulin (63.33%) and yielded neoglycoproteins with a poor to moderate degree of modification based on the percentage of available amine residues modified with CA. Only SS obtained a quantitative yield of polysialylation. Introduction of the anionic detergent sodium dodecyl sulphate (SDS) into the coupling reaction seemed to enhance polysialylation and afforded bioconjugates with 1.5-3.0 fold increase in CA content. Size exclusion chromatography and electrophoresis were used to characterise and indicate the emergence of the neoglycoproteins. In vitro biological potency was mostly preserved for catalase (63-66%), IgG2a (82-94%) and aprotinin (59-87%) modified by either method of polysialylation. Furthermore, in vivo mean residence times of polysialylated and SDS-modified polysialylated IgG (45.46- 51.81h), aprotinin (22.23-24.73h) and insulin (22.81-23.26h) were significantly increased in comparison with their native counterparts. Polysialylation appears to confer stability to the biotherapeutics, maintain potency, delay plasma clearance, thereby improving their therapeutic potential in vivo.
Phase separation of Polycomb-repressive complex 1 is governed by a charged disordered region of CBX2 (2019)

Mammalian development requires effective mechanisms to repress genes whose expression would generate inappropriately specified cells. The Polycomb-repressive complex 1 (PRC1) family complexes are central to maintaining this repression. These include a set of canonical PRC1 complexes, each of which contains four core proteins, including one from the CBX family. These complexes have been shown previously to reside in membraneless organelles called Polycomb bodies, leading to speculation that canonical PRC1 might be found in a separate phase from the rest of the nucleus. We show here that reconstituted PRC1 readily phase-separates into droplets in vitro at low concentrations and physiological salt conditions. This behavior is driven by the CBX2 subunit. Point mutations in an internal domain of <i>Cbx2</i> eliminate phase separation. These same point mutations eliminate the formation of puncta in cells and have been shown previously to eliminate nucleosome compaction in vitro and generate axial patterning defects in mice. Thus, the domain of CBX2 that is important for phase separation is the same domain shown previously to be important for chromatin compaction and proper development, raising the possibility of a mechanistic or evolutionary link between these activities.
Effective Preparation of O-Succinimidyl-2- (tert-butoxycarbonylamino)ethylcarbamate Derivatives from β-Amino Acids. Application to the Synthesis of Urea-Containing Pseudopeptides and Oligoureas (1999)

International audience
Serologic Classification of Chimpanzee Adenoviruses by Hemagglutination and Hemagglutination Inhibition (1969)

Abstract Twenty-two strains of viruses, each possessing adenovirus complement-fixing antigen and each derived from fecal specimens of chimpanzees, have been classified by their hemagglutinating properties into three major subgroups. Subgroup I is composed of eight strains which cause hemagglutination of rhesus or vervet monkey erythrocytes; subgroup II consists of 12 strains which agglutinate selected Sprague-Dawley rat erythrocytes in the presence of heterotypic immune serum to members of the Rosen subgroup III of human adenoviruses; and finally, chimpanzee subgroup III is composed of two strains which fail to agglutinate monkey, rat, guinea pig, or human type O erythrocytes. HAI reciprocal tests suggest that all eight of the subgroup I strains are related to prototype C-1 chimpanzee adenovirus, as well as to human adenovirus type 16. Six strains of subgroup II are closely antigenically related to each other and to human adenovirus type 5 by HAI. Four additional strains are partially cross-reactive in HAI tests with human adenovirus type 2 and highly cross-reactive with one another. The remaining two strains of subgroup II apparently represent previously unreported serotypes without relationships to known adenoviruses or to each other, as demonstrable by HAI techniques. Evidence is presented that the 22 strains represent a total of at least seven distinct chimpanzee serotypes of adenovirus.
Sema4D induces angiogenesis through Met recruitment by Plexin B1 (2005)

Semaphorins, a large family of membrane-bound and secreted proteins, signal through their transmembrane receptors, the plexins. Semaphorins and plexins share structural homologies with scatter factor receptors, a family of tyrosine kinase receptors for which Met is the prototype. Semaphorins have been studied primarily in the developing nervous system, where they act as repelling cues in axon guidance. However, they are widely expressed in several tissues, and their role in epithelial morphogenesis has been recently established. Not much is known about their role in angiogenesis, a key step during embryonic development and adulthood. Here we demonstrate that a semaphorin, Sema4D, is angiogenic in vitro and in vivo and that this effect is mediated by its high-affinity receptor, Plexin B1. Moreover, we prove that biologic effects elicited by Plexin B1 require coupling and activation of the Met tyrosine kinase. In sum, we identify a proangiogenic semaphorin and provide insight about the signaling machinery exploited by Plexin B1 to control angiogenesis.
Labeling of Cerebral AmyloidIn Vivowith a Monoclonal Antibody (1994)

We assessed the ability of a murine monoclonal antibody to bind selectively to beta-amyloid in the brains of living nonhuman primates. To circumvent the blood-brain barrier, we injected unlabeled antibody 10D5 (murine whole IgG1 and/or Fab fragments) into the cerebrospinal fluid of the cisterna magna in three aged monkeys. A control animal was given an intracisternal injection of nonimmune mouse whole IgG plus Fab. Twenty-four hours later, the animals were perfused and prepared for immunohistochemical detection of bound murine immunoglobulin in brain. All three experimental animals showed selective binding of 10D5 to approximately 5-15% of amyloid deposits in cerebral cortex, primarily near the cortical surface. There was no labeling in the control animal. In vivo-labeled deposits were confirmed to be beta-amyloid by electron microscopy and by in vitro immunohistochemistry in adjacent sections. The animals tolerated the injection well, although some polymorphonuclear leukocytes infiltrated portions of the subarachnoid space and superficial neocortex. These results provide the first demonstration that it may be feasible to selectively direct a tagged monoclonal antibody to beta-amyloid in the brain for therapeutic or diagnostic purposes. With enhancement of labeling efficiency, the method also may be useful for studying the progression of beta-amyloidosis in experimental animals using emission tomography.
Synthesis of 3-(3,4-dimethoxyphenyl)-1 H-1,2,4-triazole-5-thiol and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole derivatives exhibiting anti-inflammatory activity. (2001)

New 1-acylderivatives of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazole (5c-f, 6d-f) were synthesized by the acylation of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazoles (3, 4) with acyl chlorides. The compounds 3, 4 were obtained by the alkylation of 3-(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-5-thiol (2) sodium salt with alkyl iodides. Compound 2 and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole (8) were prepared by the treatment of 3,4-dimethoxybenzoylthiosemicarbazide (1) with sodium hydroxide or acetyl chloride (and then sodium hydroxide), respectively. Related 2-acylamino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazoles (7c, e, f) were synthesized by the acylation of compound 8 with acyl chlorides. 3-(3,4-Dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thione (9) was N-acylated with acyl chlorides or S-methylated with iodomethane to give 1-acyl-3-(3,4-dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H- 1,2,4-triazole-5-thiones (10a, b) or 3-(3,4-dimethoxyphenyl)-5-methylthio-4-phenyl-4H-1,2,4-triazole (11) respectively. The synthesized compounds 6d, 7a, c, 10a, b, 11 exhibit anti-inflammatory activity.
Microsoft Olap Unleashed (1999)

From the Publisher:
Microsoft OLAP Unleashed offers professional-level expertise and an in-depth explanation of the latest in multidimensional database management. It contains an entire section on MDX, the programming language of OLAP. MS OLAP Unleashed details real-world uses, how to prepare data, and how to implement an OLAP system. Topics include preparing data, creating cubes, using PivotTable Service, OLAP programming, using Excel as client, server security, real-world examples, managing a data warehouse MDX reference, and system.
Full-chip lithography simulation and design analysis: how OPC is changing IC design (2005)

Ten years ago Model-Based OPC (MB-OPC) was a research project of questionable usefulness, seen possibly as a fix until the next generation stepper was available. Today MB-OPC is one of the key technologies enabling 90nm production. In that brief span many technological challenges were resolved to allow MB-OPC to be performed on full chip layout with manageable computer resources and turnaround times. As MB-OPC has transitioned from a research to a production activity, several organizational challenges have arisen. Defining the steps and procedures involved in creating OPC techfiles has been necessary to allow the increased workload to be shared. Testing and documenting the OPC recipes has become a necessary discipline to ensure quality and repeatability in manufacturing. In addition to the engineers who create the OPC recipes, we now also have Fab OPC Engineers to support OPC verification and continuous improvement activities. Furthermore, the OPC process, i.e. the modification of the layout to account for the manufacturing process, has provided a tantalizing link between the design, process development and yield engineering communities. The EDA framework appears to provide a common language, however we are just beginning to ask the right questions to allow us to unlock the potential that appears so close. The paper will begin with a historical overview of the development of MB-OPC and describe the seemingly overwhelming obstacles, both computational and in mask fabrication that had to be overcome. The second part of the paper will deal with some of the problems that have arisen as MB-OPC has become a critical technology for high volume production. The final part of the paper will discuss how MB-OPC has changed the way that Lithography, Integration and Design engineers interact. Some examples of design/process interaction will be given as well as a discussion of future developments.
Aryl Phosphoramidate Derivatives of d4T Have Improved Anti-HIV Efficacy in Tissue Culture and May Act by the Generation of a Novel Intracellular Metabolite (1996)

New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.
Similarity of event sequences (2002)

Sequences of events are an important form of data that occurs in many application domains, such as telecommunications, biostatistics, user interface design, etc. We present a simple model for measuring the similarity of event sequences, and show that the resulting measure of distance can be efficiently computed using a form of dynamic programming.
Tango: a framework and system for algorithm animation (1990)

The role of animation in understanding and evaluating programs and developing new programs is discussed. A framework for algorithm animation, called Tango, and a system based on that framework are introduced. Related work is reviewed, and the conceptual framework on which Tango is based is examined. The implementation of the Tango system is described. The first-fit bin-packing algorithm is animated to illustrate how the path-transition paradigm simplifies algorithm animation.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
A parametric loudspeaker—applied examples (1994)

Abstract A parametric loudspeaker using the self‐demodulation of finite‐amplitude ultrasound has a sharper directivity than a conventional loudspeaker of the same aperture size. This is because of the formation of the end‐fire array with virtual sound sources which are generated in the ultrasound beam. In general, when the aperture becomes smaller, the difference in directivity appears clearly. This article describes a theoretical prediction of the optimum frequency of primary ultrasound waves to develop a transmitter with small aperture and compares the theory and experiment using an 11‐cm diameter parametric loudspeaker. The possibility of practical use for guidance equipment such as an audible pedestrian signal also is discussed. Furthermore, using large‐aperture parametric loudspeakers, an experiment is carried out in a reverberant tunnel to confirm the effectiveness in the improvement of speech articulation.
Novel Cyanobacterial Biosensor for Detection of Herbicides (2002)

The aim of this work was to generate a cyanobacterial biosensor that could be used to detect herbicides and other environmental pollutants. A representative freshwater cyanobacterium, Synechocystis sp. strain PCC6803, was chromosomally marked with the luciferase gene luc (from the firefly Photinus pyralis) to create a novel bioluminescent cyanobacterial strain. Successful expression of the luc gene during growth of Synechocystis sp. strain PCC6803 cultures was characterized by measuring optical density and bioluminescence. Bioluminescence was optimized with regard to uptake of the luciferase substrate, luciferin, and the physiology of the cyanobacterium. Bioassays demonstrated that a novel luminescent cyanobacterial biosensor has been developed which responded to a range of compounds including different herbicide types and other toxins. This biosensor is expected to provide new opportunities for the rapid screening of environmental samples or for the investigation of potential environmental damage.
Accurately Mapping Image Charge and Calibrating Ion Velocity in Charge Detection Mass Spectrometry (2020)

Image charge detection is the foundation of charge detection mass spectrometry (CDMS). The mass-to-charge ratio, <i>m</i>/<i>z</i>, of a highly charged ion or particle is determined by measuring the particle's charge and velocity. Charge is typically determined from a calibrated image charge signal, and the particle velocity is calculated using the peaks from the shaped signal as they relate to the particle position and time-of-flight through a detector of known length. Although much has been done to improve the charge accuracy in CDMS, little has been done to address the inconsistencies in the particle velocity measurements and the interpretation of peak position and effective electrode length. In this work, we combine SIMION ion trajectory software and the Shockley-Ramo theorem to accurately determine the effective electrode length, peak position, and shape of the signal peaks. Six model charge detector geometries were examined with this method and evaluated in laboratory experiments. Experimental results in all cases agreed with the simulations. Using a charge detector with multiple, 12.7 mm-long cylindrical electrodes, experimental velocities across and between electrodes agreed within 0.25% relative standard deviation (RSD) when this method was used to correct for effective electrode lengths, corresponding to an uncertainty in the effective electrode length of only 40 μm. For a detector with multiple electrodes and varied electrode spacing, experiments showed that the peak amplitude and shape vary with the geometry and with the particle path through the detector, whereas all peak areas agreed to within 2.3% RSD. For a charge detector made of two printed circuit boards, the velocities agreed within 0.44% RSD using the calculated effective electrode length.
Cortical spreading depression activates and upregulates MMP-9 (2004)

Cortical spreading depression (CSD) is a propagating wave of neuronal and glial depolarization and has been implicated in disorders of neurovascular regulation such as stroke, head trauma, and migraine. In this study, we found that CSD alters blood-brain barrier (BBB) permeability by activating brain MMPs. Beginning at 3–6 hours, MMP-9 levels increased within cortex ipsilateral to the CSD, reaching a maximum at 24 hours and persisting for at least 48 hours. Gelatinolytic activity was detected earliest within the matrix of cortical blood vessels and later within neurons and pia arachnoid (≥3 hours), particularly within piriform cortex; this activity was suppressed by injection of the metalloprotease inhibitor GM6001 or in vitro by the addition of a zinc chelator (1,10-phenanthroline). At 3–24 hours, immunoreactive laminin, endothelial barrier antigen, and zona occludens-1 diminished in the ipsilateral cortex, suggesting that CSD altered proteins critical to the integrity of the BBB. At 3 hours after CSD, plasma protein leakage and brain edema developed contemporaneously. Albumin leakage was suppressed by the administration of GM6001. Protein leakage was not detected in MMP-9–null mice, implicating the MMP-9 isoform in barrier disruption. We conclude that intense neuronal and glial depolarization initiates a cascade that disrupts the BBB via an MMP-9–dependent mechanism.