gebhart/patrepeval huggingface dataset:
Epitope‐Targeted Macrocyclic Peptide Ligand with Picomolar Cooperative Binding to Interleukin‐17F (2018)

The IL-17 cytokine family is associated with multiple immune and autoimmune diseases and comprises important diagnostic and therapeutic targets. This work reports the development of epitope-targeted ligands designed for differential detection of human IL-17F and its closest homologue IL-17A. Non-overlapping and unique epitopes on IL-17F and IL-17A were identified by comparative sequence analysis of the two proteins. Synthetic variants of these epitopes were utilized as targets for in situ click screens against a comprehensive library of synthetic peptide macrocycles with 5-mer variable regions. Single generation screens yielded selective binders for IL-17F and IL-17A with low cross-reactivity. Macrocyclic peptide binders against two distinct IL-17F epitopes were coupled using variable length chemical linkers to explore the physical chemistry of cooperative binding. The optimized linker length yielded a picomolar affinity binder, while retaining high selectivity. The presented method provides a rational approach towards targeting discontinuous epitopes, similar to what is naturally achieved by many B cell receptors.
A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands (2017)

The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro], and may be further developed to generate novel melanocortin probes and ligands for understanding and treating obesity.
Composite free layer for high density magnetic random access memory with lower spin transfer current (2006)

A magnetic tunnel junction (MTJ) structure with a composite free layer consisting of a nanocurrent-channel (NCC) layer sandwiched by two CoFe layers was proposed and investigated. The NCC layer increased the local spin current density inside the free layer and thus enhanced the writing capability for MTJ devices. In comparison with the conventional MTJ design with a single free layer, the intrinsic critical switching current density was reduced from 2.4×107to8.5×106A∕cm2 by using the composite free layer. On the other hand, the thermal stability factor of the composite free layer, KuV∕kBT, is around 149, which is almost the same as the value (159) for the MTJ device with a single free layer. The MTJ structure with the composite free layer is a candidate to solve the scaling problem for high density magnetic random access memory.
Sleeping tongue: current perspectives of genioglossus control in healthy individuals and patients with obstructive sleep apnea (2018)

The focus of this review was on the genioglossus (GG) muscle and its role in maintaining upper airway patency in both healthy individuals and obstructive sleep apnea (OSA) patients. This review provided an overview of GG anatomy and GG control and function during both wakefulness and sleep in healthy individuals and in those with OSA. We reviewed evidence for the role of the GG in OSA pathogenesis and also highlighted abnormalities in GG morphology, responsiveness, tissue movement patterns and neurogenic control that may contribute to or result from OSA. We summarized the different methods for improving GG function and/or activity in OSA and their efficacy. In addition, we discussed the possibility that assessing the synergistic activation of multiple upper airway dilator muscles may provide greater insight into upper airway function and OSA pathogenesis, rather than assessing the GG in isolation.
Improvement of Intestinal Absorption of Peptide Drugs by Glycosylation: Transport of Tetrapeptide by the Sodium Ion-Dependent D-Glucose Transporter (1998)

A tetrapeptide (Gly-Gly-Tyr-Arg, GGYR), which is not transported by di- or tripeptide transporters, was glycosylated with p-(succinylamido)phenyl alpha- or beta-D-glucopyranoside (alpha,beta-SAPG) to investigate whether these glycosylated molecules are transported by the Na+-dependent D-glucose transporter. Their uptake into brush border membrane vesicles (BBMVs) and transport through the intestinal membrane were examined using the rapid filtration technique and the everted sac method. It was observed that glycosylation at the alpha-amino position of GGYR increased resistance to aminopeptidase activity and inhibited its degradation. When alpha- and beta-SAPG-GGYR were incubated with BBMVs, overshoot uptake was observed about 2 min after the start of incubation in the presence of an inward Na+ gradient. This uptake remained unaffected by the addition of GGYR while it was significantly inhibited when Na+ was replaced with K+ or alpha- and beta-SAPG-GGYR were incubated with BBMVs at 4 degrees C. Uptake was also markedly inhibited either with 1 mM phloridzin or 10 mM D-glucose. These findings suggested that the Na+-dependent glucose transporter (SGLT-1) played an important role in the uptake of both alpha- and beta-SAPG-GGYR into BBMVs. A comparison of alpha- with beta-SAPG-GGYR revealed that the amount of beta-SAPG-GGYR taken up was greater than that of alpha-SAPG-GGYR. From the everted sac method data, it was shown that the elimination clearance from the mucosal side, CLel, and permeation clearance to the serosal side, CLp, were 15.82+/-6.83 and 0.83+/-0.06 microL/min/cm for alpha-SAPG-GGYR and 44.52+/-3.61 and 3.50+/-0.81 microL/min/cm for beta-SAPG-GGYR, respectively, and that alpha-SAPG-GGYR was more resistant to enzymatic degradation than beta-SAPG-GGYR. Permeation of both alpha- and beta-SAPG-GGYR was inhibited in the presence of D-glucose and in the absence of a Na+ gradient, suggesting that both alpha- and beta-SAPG-GGYR were transported by the Na+-dependent D-glucose transporter. The permeation clearance transported by the Na+-dependent D-glucose transporter, (CLp)Na+, of beta-SAPG-GGYR was about 5 times greater than that for alpha-SAPG-GGYR. This result may be ascribable to the fact that the beta-form of glucose has higher affinity to SGLT-1 than the alpha-form. The results of the present study encourage further investigations on improvements in intestinal absorption of peptide drugs by glycosylation.
Morphology and Phase Segregation of Spin-Casted Films of Polyfluorene/PCBM Blends (2007)

In this study the morphology of spin-casted films of polymers blended with [6,6]-phenyl C61-butyric acid methyl ester (PCBM) has been studied. It was found that the lateral structure formation in the films is favored by rapid solvent evaporation and strong polymer−PCBM repulsion. The formation of homogeneous films is favored by slow evaporation and weak polymer−PCBM repulsion. The effect of solvent evaporation rate is the opposite of what is found for spin-casting polymer−polymer blends. The results can be explained by the kinetics of phase separation and the phase behavior involving limited solubility and crystallization of PCBM.
Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor (1992)

Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
High-affinity oligoclonal TCRs define effective adoptive T cell therapy targeting mutant KRAS-G12D (2020)

Complete cancer regression occurs in a subset of patients following adoptive T cell therapy (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TILs). However, the low success rate presents a great challenge to broader clinical application. To provide insight into TIL-based immunotherapy, we studied a successful case of ACT where regression was observed against tumors carrying the hotspot mutation G12D in the KRAS oncogene. Four T cell receptors (TCRs) made up the TIL infusion and recognized two KRAS-G12D neoantigens, a nonamer and a decamer, all restricted by human leukocyte antigen (HLA) C*08:02. Three of them (TCR9a, 9b, and 9c) were nonamer-specific, while one was decamer-specific (TCR10). We show that only mutant G12D but not the wild-type peptides stabilized HLA-C*08:02 due to the formation of a critical anchor salt bridge to HLA-C. Therapeutic TCRs exhibited high affinities, ranging from nanomolar to low micromolar. Intriguingly, TCR binding affinities to HLA-C inversely correlated with their persistence in vivo, suggesting the importance of antigenic affinity in the function of therapeutic T cells. Crystal structures of TCR-HLA-C complexes revealed that TCR9a to 9c recognized G12D nonamer with multiple conserved contacts through shared CDR2β and CDR3α. This allowed CDR3β variation to confer different affinities via a variable HLA-C contact, generating an oligoclonal response. TCR10 recognized an induced and distinct G12D decamer conformation. Thus, this successful case of ACT included oligoclonal TCRs of high affinity recognizing distinct conformations of neoantigens. Our study revealed the potential of a structural approach to inform clinical efforts in targeting KRAS-G12D tumors by immunotherapy and has general implications for T cell-based immunotherapies.
Microwave Synthesized NaTi2(PO4)3as an Aqueous Sodium-Ion Negative Electrode (2013)

Carbon-coated NaTi2(PO4)3 was successfully synthesized via a rapid microwave-assisted method and was found to have promising electrochemical function in a neutral pH Na2SO4 aqueous electrolyte. The effects of various processing parameters, including precursor ball mill time, microwave irradiation parameters, and graphite precursor concentration, on the physical and electrochemical properties of the synthesized NaTi2(PO4)3. To further study electrochemical performance, a full test cell consisting of NaTi2(PO4)3/1 M Na2SO4/Na0.44MnO2 was assembled. The highest discharge specific capacity obtained for this material was 85 mAh/g. These results indicate that, with an appropriate amount of graphite included in the precursor mix, microwave-synthesized NaTi2(PO4)3 is a promising sodium-ion functional anode material that can be produced using an extremely appealing low-cost manufacturing process.
Algorithm-based low-power VLSI architecture for 2D mesh video-object motion tracking (2002)

The new VLSI architecture for video object (VO) motion tracking uses a novel hierarchical adaptive structured mesh topology. The structured mesh offers a significant reduction in the number of bits that describe the mesh topology. The motion of the mesh nodes represents the deformation of the VO. Motion compensation is performed using a multiplication-free algorithm for affine transformation, significantly reducing the decoder architecture complexity. Pipelining the affine unit contributes a considerable power saving. The VO motion-tracking architecture is based on a new algorithm. It consists of two main parts: a video object motion-estimation unit (VOME) and a video object motion-compensation unit (VOMC). The VOME processes two consequent frames to generate a hierarchical adaptive structured mesh and the motion vectors of the mesh nodes. It implements parallel block matching motion-estimation units to optimize the latency. The VOMC processes a reference frame, mesh nodes and motion vectors to predict a video frame. It implements parallel threads in which each thread implements a pipelined chain of scalable affine units. This motion-compensation algorithm allows the use of one simple warping unit to map a hierarchical structure. The affine unit warps the texture of a patch at any level of hierarchical mesh independently. The processor uses a memory serialization unit, which interfaces the memory to the parallel units. The architecture has been prototyped using top-down low-power design methodology. Performance analysis shows that this processor can be used in online object-based video applications such as MPEG-4 and VRML.
Development of the blood vessels and extracellular spaces during postnatal maturation of rat cerebral cortex (1970)

Abstract As part of a larger study of the development of postnatal rat cerebral cortex, this report deals with the maturation of the cortex as a tissue from birth to twenty‐one days of age. The changes in the numerical density of cells and blood vessels and the thickness of the cortex at successive ages were followed on light micrographs, and both were related to the ultrastructural observations on routine electron microscopic preparations. The maturation of the cortex is divided into two periods: The first ten days during which the growth to adult dimensions occurs and few patent blood vessels but large extracellular spaces are to be found, and the second ten days in which the majority of the vessels develop patent lumina, the perivascular sheath of astrocyte end‐feet develops, and the large extracellular spaces disappear concomitant with the maturation of the neuropil. The blood vessels appear to develop during the first ten days as solid cords of mesodermal elements which form a network of primordial vessels with thick walls and slit‐like lumina containing a flocculent material. The formation of a blood filled, patent lumen apparently occurs synchronously over a brief period of time for the majority of the vessels during the early part of the second ten‐day period. The basal lamina is ill‐defined initially but takes on mature appearance parallel with the development of the perivascular glial sheath. The volume of the extracellular space was found to be largest during the phase of rapid growth of axons and dendrites when few patent vessels exist. The disappearance of these large extracellular spaces during maturation of the blood vessels and neuropil is discussed in terms of the possible artifactitious nature of these spaces in both immature and mature cortex.
Co‐expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions (1998)

Atherosclerosis is a fibroproliferative disease of the arterial intima. It was recently found that wild-type p53 (wt p53) accumulates in human atherosclerotic tissue. Wt p53 is a cell cycle regulator involved in DNA repair, DNA synthesis, cell differentiation, and apoptosis and might therefore make an important contribution to the cellularity of atherosclerotic plaques. The product of the MDM2 gene is a nuclear protein which forms a complex with p53, thereby inhibiting the negative regulatory effects of wt p53 on cell cycle progression. In order to address a potential role of the interaction of p53 with MDM2 for the regulation of cellularity in atherosclerotic tissue, 22 carotid atheromatous plaques from patients undergoing endarterectomy were studied to determine the presence of p53 immunoreactivity (IR), MDM2 IR, cell proliferation as evidenced by MIB1/Ki-67 IR and DNA fragmentation by in situterminal transferase-mediated dUTP 3′ end labelling (TUNEL), as a marker for apoptosis. p53 IR localized to areas with evidence of chronic inflammation (22/22) and was observed in virtually all cell types in 68·79±7·51 per cent of the nuclei. p53 staining in the control tissue from human internal mammary arteries was present in 0·2±0·29 per cent of the cells (P≤0·002). MDM2 IR was present in all cases (22/22) in macrophages and smooth muscle cells (SMCs) in 60·53±8·32 per cent of the nuclei (controls: 0·8±0·65 per cent, P≤0·002) and co-localized with p53 IR as shown by examination of adjacent sections and by double immunofluorescence labelling. Importantly, co-immunoprecipitation and western blot analysis revealed that p53 and MDM2 were physically associated, indicating that MDM2–p53 complex formation takes place in vivoin human atherosclerotic tissue. Positive TUNEL staining and MIB1/Ki-67 IR present in 3·01±1·27 per cent of the nuclei (controls: 0 per cent, P≤0·002) localized to the same plaque compartments as p53 IR and MDM2 IR. Thus, the fate of cells with p53 accumulation may depend on the interaction and the stoichiometry of the p53 and MDM2 proteins. Cells were indeed found with strong p53 accumulation and nuclear morphology typical for apoptosis and there were a few MIB1/Ki-67-positive cells with co-expression of MDM2, indicating a possible role for MDM2 in reversing the negative regulatory effects of p53 for cell cycle progression. The nuclear co-localization of p53 IR with MDM2 IR and the co-immunoprecipitation assay indicate the presence of p53–MDM2 complex formation in vivo in human atherosclerotic tissue. The destiny of individual p53 and MDM2-co-expressing cells either to undergo p53-dependent apoptosis or to re-enter the cycle of cell proliferation may depend on the relative ratios of the two proteins. p53 and MDM2 may therefore play an important role in regulating cellularity and inflammatory activity in human atherosclerotic plaques. © 1998 John Wiley & Sons, Ltd.
Collagen‐Poly(methyl methacrylate) graft copolymers: Effect of aqueous organic solvent system and salts on copolymer composition (1974)

Abstract Collagen‐poly(methyl methacrylate) (PMMA) graft copolymers were prepared in a number of aqueous/organic solvent systems and in the presence of neutral salts using ceric ammonium nitrate as initiator. The composition of the collagen‐methyl methacrylate graft copolymers was studied by hydrolyzing the collagen backbone and measuring the molecular weights of the grafted PMMA branches. In water/methanol grafting media the molecular weights of the PMMA branches showed a maximum at a methanol concentration of 25% and then decreased with further increase in methanol concentration. Even though the percent grafting registered a sharp fall with increasing concentration of methanol, the number of grafting sites remained more or less constant and was almost the same as that obtained in aqueous medium. Other aqueous/organic solvent systems gave more grafted chains than those prepared in water alone, and these were of lower molecular weight. Anions such as sulphate and chloride were found to have more influence than nitrate in decreasing the number of grafting sites.
Label-free cell separation and sorting in microfluidic systems (2010)

Cell separation and sorting are essential steps in cell biology research and in many diagnostic and therapeutic methods. Recently, there has been interest in methods which avoid the use of biochemical labels; numerous intrinsic biomarkers have been explored to identify cells including size, electrical polarizability, and hydrodynamic properties. This review highlights microfluidic techniques used for label-free discrimination and fractionation of cell populations. Microfluidic systems have been adopted to precisely handle single cells and interface with other tools for biochemical analysis. We analyzed many of these techniques, detailing their mode of separation, while concentrating on recent developments and evaluating their prospects for application. Furthermore, this was done from a perspective where inertial effects are considered important and general performance metrics were proposed which would ease comparison of reported technologies. Lastly, we assess the current state of these technologies and suggest directions which may make them more accessible.
Tracking oligodendrocytes during development and regeneration (2001)

Over the past decade, advances in strategies to tag cells have opened new avenues for examining the development of myelin-forming glial cells and for monitoring transplanted cells in animal models of myelin insufficiency. The strategies for labelling glial cells have encompassed a range of genetic modifications as well as methods for directly attaching labels to cells. Genetically modified oligodendrocytes have been engineered to express enzymatic (e.g., beta-galactosidase, alkaline phosphatase), naturally fluorescent (e.g., green fluorescent protein), and antibiotic resistance (e.g., neomycin, zeomycin) reporters. Genes have been introduced in vivo and in vitro with viral or plasmid vectors to somatically label glial cells. To generate germ-line transmission of tagged oligodendrocytes, transgenic mice have been created both by direct injection into mouse fertilized eggs and by "knock-in" of reporters targetted to myelin gene loci in embryonic stem cells. Each experimental approach has advantages and limitations that need to be considered for individual applications. The availability of tagged glial cells has expanded our basic understanding of how oligodendrocytes are specified from stem cells and should continue to fill in the gaps in our understanding of how oligodendrocytes differentiate, myelinate, and maintain their myelin sheaths. Moreover, the ability to select oligodendrocytes by virtue of their acquired antibiotic resistance has provided an important new tool for isolating and purifying oligodendrocytes. Tagged glial cells have also been invaluable in evaluating cell transplant therapies in the nervous system. The tracking technologies that have driven these advances in glial cell biology are continuing to evolve and present new opportunities for examining oligodendrocytes in living systems. Microsc. Res. Tech. 52:766-777, 2001. Published 2001 Wiley-Liss, Inc.
Ribosome biogenesis factor Tsr3 is the aminocarboxypropyl transferase responsible for 18S rRNA hypermodification in yeast and humans (2016)

The chemically most complex modification in eukaryotic rRNA is the conserved hypermodified nucleotide N1-methyl-N3-aminocarboxypropyl-pseudouridine (m(1)acp(3)Ψ) located next to the P-site tRNA on the small subunit 18S rRNA. While S-adenosylmethionine was identified as the source of the aminocarboxypropyl (acp) group more than 40 years ago the enzyme catalyzing the acp transfer remained elusive. Here we identify the cytoplasmic ribosome biogenesis protein Tsr3 as the responsible enzyme in yeast and human cells. In functionally impaired Tsr3-mutants, a reduced level of acp modification directly correlates with increased 20S pre-rRNA accumulation. The crystal structure of archaeal Tsr3 homologs revealed the same fold as in SPOUT-class RNA-methyltransferases but a distinct SAM binding mode. This unique SAM binding mode explains why Tsr3 transfers the acp and not the methyl group of SAM to its substrate. Structurally, Tsr3 therefore represents a novel class of acp transferase enzymes.