gebhart/patrepeval huggingface dataset:
Synthetic lactulose amines: novel class of anticancer agents that induce tumor-cell apoptosis and inhibit galectin-mediated homotypic cell aggregation and endothelial cell morphogenesis (2005)

Galectins, a family of structurally related carbohydrate-binding proteins, contribute to different events associated with cancer biology, including apoptosis, homotypic cell aggregation, angiogenesis and tumor-immune escape. To interfere with galectin-carbohydrate interactions during tumor progression, a current challenge is the design of specific galectin inhibitors for therapeutic purposes. Here, we report the synthesis of three novel low molecular weight synthetic lactulose amines (SLA): (1) N-lactulose-octamethylenediamine (LDO), (2) N,N'-dilactulose-octamethylenediamine (D-LDO), and (3) N,N'-dilactulose-dodecamethylenediamine (D-LDD). These compounds showed a differential ability to inhibit binding of galectin-1 and/or galectin-3 to the highly glycosylated protein 90K in solid-phase assays. In addition, each compound demonstrated selective regulatory effects in different events linked to tumor progression including tumor-cell apoptosis, homotypic cell aggregation, and endothelial cell morphogenesis. Our results suggest that galectin inhibitors with subtle differences in their carbohydrate structures may be potentially used to specifically block different steps of tumor growth and metastasis.
Alpha 1 Anti-Trypsin: One Protein, Many Functions (2012)

α-1 anti-trypsin (AAT) is the most abundant circulating serine protease inhibitor (serpin) and an acute phase reactant. Systemic deficiency in AAT (AATD) due to genetic mutations can result in liver failure and chronic lung disease such as emphysema. Considered the prototypic serpin, the emphysema observed in patients with AATD, consisting of progressive destruction of the alveoli and small airway structures, formed the basis of the protease/anti-protease imbalance theory of chronic obstructive pulmonary disease (COPD). Over the past decade, however, investigations of AATD have described multiple functions of AAT beyond those generally attributed to its antiprotease activity. Evidence now suggests that AAT plays an important role in modulating immunity, inflammation, proteostasis, apoptosis, and possibly cellular senescence programs. When integrated in vivo, these processes contribute to the lung maintenance program which preserves the lung despite a constant bombardment by damage associated molecular patterns (DAMPs) and/or pathogenassociated molecular patterns (PAMPs) initiated by cigarette smoke, pollutants, or infections. In this review, we discuss the clinical aspects of AATD as they pertain to emphysema; including similarities and differences to cigarette smoke-induced emphysema. Examining the lung maintenance program, we next consider the multiple mechanisms of airspace destruction and explore the role AATD contributes. Finally, we consider the data regarding treatment of AATD, including AAT supplementation and its current limitations, and suggest further avenues of research informed by the multiple functions of AAT.
Cellular transcription factor binds to adenovirus early region promoters and to a cyclic AMP response element (1988)

We have analyzed the sequences that regulate the transcription of adenovirus type 5 early region 4 (E4). A region located immediately upstream of the E4 TATA box is required for efficient E4 transcription in vitro and in vivo. A cellular transcription factor, termed ETF-A, binds to this region. ETF-A also binds to additional sites in the E4 5'-flanking region, including the adenovirus terminal repeat, as well as to the adenovirus early region 2 promoter region and the adeno-associated virus early promoter region. A repeated sequence motif is found in each binding domain. The same factor binds to a region upstream of a cellular gene that contains a cyclic AMP response element. Consistent with this result, E4 expression is induced in vivo by cyclic AMP. Two other regions further upstream of the E4 initiation site also contribute to efficient E4 expression. These domains are functionally redundant and contain binding sites for ETF-A. One domain is the adenovirus terminal repeat, which has strong promoter activity in vitro and in vivo.
Differential targeting of secretory lysosomes and recycling endosomes in mast cells revealed by patterned antigen arrays (2007)

Polarized response towards a contact interface is a common theme in intercellular signaling. To visualize spatial regulation of stimulated secretion within a contact region, we exposed IgE-sensitized rat basophilic leukemia (RBL) mast cells to a surface that was patterned on the microm scale with hapten-containing lipid bilayers to activate cell surface IgE-receptor complexes. We find that, within 10 minutes of stimulation, fusion of individual secretory lysosomes is targeted towards the cell-substrate interface, but is spatially segregated from the patterned bilayers and receptor signaling complexes. By contrast, stimulated outward trafficking of recycling endosomes is preferentially targeted towards the patterned bilayers. High spatial resolution of both antigen presentation in these arrays and detection of exocytotic events provides direct evidence for the heterogeneity of polarized responses.
Interleukin 15 and Its Receptor (2007)

Interleukin 15 (IL-15) is a member of the four-helix bundle cytokine family that shares many in vitro biological activities with IL-2. Previous work demonstrated that IL-15 utilizes the beta and gamma chains of the IL-2 receptor (IL-2R), and that these are essential for IL-15-mediated signal transduction. However, several lines of evidence indicated the existence of an additional, IL-15-specific receptor component. An IL-15 binding chain was identified on a murine T cell clone, and direct expression cloning was used to isolate the corresponding cDNA. The predicted structure of this protein shows sequence similarity to the IL-2R alpha chain. Transfection of this cDNA into a murine, IL-3-dependent myeloid cell line, 32D-01, conferred IL-15 binding and, together with transfection of the IL-2R beta chain, rendered the cells responsive to IL-15 stimulation. This experiment confirmed that the IL-15 binding chain is part of the IL-15 receptor, and it is designated as the IL-15R alpha subunit. The expression pattern of the IL-15R alpha mRNA is distinct from that of IL-2R alpha mRNA. Recombinant expression of a soluble form of IL-15R alpha demonstrated that it is a potent inhibitor of IL-15 biological activity.
The UnMousePad (2009)

Recently, there has been great interest in multi-touch interfaces. Such devices have taken the form of camera-based systems such as Microsoft Surface [de los Reyes et al. 2007] and Perceptive Pixel's FTIR Display [Han 2005] as well as hand-held devices using capacitive sensors such as the Apple iPhone [Jobs et al. 2008]. However, optical systems are inherently bulky while most capacitive systems are only practical in small form factors and are limited in their application since they respond only to human touch and are insensitive to variations in pressure [Westerman 1999]. We have created the UnMousePad, a flexible and inexpensive multitouch input device based on a newly developed pressure-sensing principle called Interpolating Force Sensitive Resistance. IFSR sensors can acquire high-quality anti-aliased pressure images at high frame rates. They can be paper-thin, flexible, and transparent and can easily be scaled to fit on a portable device or to cover an entire table, floor or wall. The UnMousePad can sense three orders of magnitude of pressure variation, and can be used to distinguish multiple fingertip touches while simultaneously tracking pens and styli with a positional accuracy of 87 dpi, and can sense the pressure distributions of objects placed on its surface. In addition to supporting multi-touch interaction, IFSR is a general pressure imaging technology that can be incorporated into shoes, tennis racquets, hospital beds, factory assembly lines and many other applications. The ability to measure high-quality pressure images at low cost has the potential to dramatically improve the way that people interact with machines and the way that machines interact with the world.
Expression and Purification of the Extracellular Ligand Binding Region of Metabotropic Glutamate Receptor Subtype 1 (1998)

Each metabotropic glutamate receptor possesses a large extracellular domain that consists of a sequence homologous to the bacterial periplasmic binding proteins and a cysteine-rich region. Previous experiments have proposed that the extracellular domain is responsible for ligand binding. However, it is currently unknown whether the extracellular ligand binding site can bind ligands without other domains of the receptor. We began by obtaining a sufficient amount of receptor protein on a baculovirus expression system. In addition to the transfer vector that encodes the entire coding region, transfer vectors that encode portions of the extracellular domain were designed. Here, we report a soluble metabotropic glutamate receptor that encodes only the extracellular domain and retains a ligand binding characteristic similar to that of the full-length receptor. The soluble receptor secreted into culture medium showed a dimerized form. Furthermore, we have succeeded in purifying it to homogeneity. Dose-response curves of agonists for the purified soluble receptor were examined. The effective concentration for half-maximal inhibition (IC50) of quisqualate for the soluble receptor was 3.8 x 10(-8) M, which was comparable to that for the full-length receptor. The rank order of inhibition of the agonists was quisqualate >> ibotenate >/= L-glutamate approximately (1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid. These data demonstrate that a ligand binding event in metabotropic glutamate receptors can be dissociated from the membrane domain.
Vaccination with Tumor Peptide in CpG Adjuvant Protects Via IFN-γ-Dependent CD4 Cell Immunity (2002)

The low frequency of tumor Ag-specific T cells in vivo has made it challenging to directly measure their clonal sizes and cytokine signatures. We used a new generation ELISPOT approach to study the constitutive immunogenicity of the RMA tumor in syngeneic B6 mice and adjuvant-guided immunity against an MHC class II-restricted RMA peptide, H11.1. The RMA tumor was found to activate cells of the innate immune system and to induce a type 1 polarized, RMA-specific CD4 and CD8 T cell response. With clonal sizes approximately 10/10(6), the magnitude of this constitutively induced immune response did not suffice to control the tumor cell growth. In contrast, immunization with H11.1 peptide, using an immunostimulatory CpG oligonucleotide or CFA as adjuvant, engaged approximately 25- or approximately 10-fold higher clonal sizes of type 1 polarized CD4 cells, respectively. Therefore, the CpG oligonucleotide functioned as a stronger type 1 adjuvant and, unlike CFA, elicited protective immunity. The protection was IFN-gamma dependent, as it was not inducible in IFN-gamma knockout mice. Therefore, CpG adjuvant-guided induction of type 1 immunity against tumor Ags might be a promising subunit vaccination approach.
The SIRPα–CD47 immune checkpoint in NK cells (2020)

Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I-deficient target cells against SIRPα+ primary NK cells, but not against SIRPα- NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα-CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell-mediated killing of allogeneic and xenogeneic tissues.
Role of β-Arrestin in Mediating Agonist-Promoted G Protein-Coupled Receptor Internalization (1996)

beta-Arrestins are proteins that bind phosphorylated heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) and contribute to the desensitization of GPCRs by uncoupling the signal transduction process. Resensitization of GPCR responsiveness involves agonist-mediated receptor sequestration. Overexpression of beta-arrestins in human embryonic kidney cells rescued the sequestration of beta 2-adrenergic receptor (beta 2AR) mutants defective in their ability to sequester, an effect enhanced by simultaneous overexpression of beta-adrenergic receptor kinase 1. Wild-type beta 2AR sequestration was inhibited by the overexpression of two beta-arrestin mutants. These findings suggest that beta-arrestins play an integral role in GPCR internalization and thus serve a dual role in the regulation of GPCR function.
Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis (2001)

Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints. The goal of this phase-I/II study in adults with rheumatoid arthritis (RA) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed. This was a multicenter, randomized, placebo-controlled trial that evaluated the safety and tolerability of rhIL-11 in 91 patients with active RA. rhIL-11 was administered subcutaneously; patients were randomized into one of five treatment groups (ratio of rhIL-11 to placebo, 4:1). Patients were treated for 12 weeks with either 2.5 or 7.5 microg/kg of rhIL-11 or placebo twice per week or 5 or 15 microg/kg of rhIL-11 or placebo once per week. The status of each subject's disease activity in accordance with the American College of Rheumatology (ACR) criteria was assessed before, during, and after completion of administration of the study drug. Administration of rhIL-11 was well tolerated at all doses and schedules. The most frequent adverse event was a reaction at the injection site. The data suggest a statistically significant reduction in the number of tender joints (P < 0.008) at the 15 microg/kg once-weekly dose schedule but showed no overall significant benefit at the ACR criterion of a 20% response. The trial showed rhIL-11 to be safe and well tolerated at a variety of doses and schedules over a 12-week treatment period in patients with active RA. The only adverse event clearly associated with rhIL-11 administration was reaction at the injection site.
P‐37: Optical Fiber scanning as a Microdisplay source for a Wearable Low Vision Aid (2002)

Abstract Optical fibers are microfabricated and piezoelectrically vibrated to produce rectilinear scan patterns. By coupling a laser to the optical fiber and projecting the collimated light directly to the viewer's eye, the result is a proposed low‐cost, spectacle‐mounted, wearable low vision aid.
Effect of Mechanical Loading on Three-Dimensional Cultures of Embryonic Stem Cell-Derived Cardiomyocytes (2007)

Cardiomyocytes selected from murine embryonic stem cells (ESCs) using the cardiac-specific promoter alpha-myosin heavy chain were embedded into collagen and fibronectin scaffolds. A custom-built device was used to expose these constructs to mechanical loading (10% stretch at 1, 2, or 3 Hz) or no loading. Constructs were evaluated using reverse transcriptase polymerase chain reaction, histology, and immunohistochemistry. Mechanical loading significantly affected gene expression, and these changes were dependent on the frequency of stretch. A 1 Hz cyclical stretch resulted in significantly lower gene expression, whereas a 3 Hz cyclical stretch resulted in significantly greater gene expression than in unstretched controls. These constructs also developed cardiac-specific cell structures similar to those found in vivo. This study describes a 3-dimensional model to examine the direct effect of mechanical loading on the differentiation of ESC-derived cardiomyocytes embedded in a defined extracellular matrix scaffold. A technique was also developed to isolate the areas within the constructs undergoing the most homogeneous strain so that the effect of mechanical loading on gene expression could be directly evaluated. These experiments emphasize that ESC-derived cardiomyocytes are actively responding to cues from their environment and that those cues can drive phenotypic control and cardiomyocyte differentiation.
Peroxynitrite-induced luminol chemiluminescence (1993)

Vascular endothelial cells, smooth muscle cells, macrophages, neutrophils, Kupffer cells and other diverse cell types generate superoxide (O2.-) and nitric oxide (.NO), which can react to form the potent oxidant peroxynitrite anion (ONOO-). Peroxynitrite reacted with luminol to yield chemiluminescence which was greatly enhanced by bicarbonate. The quantum chemiluminescence yield of the ONOO- reaction with luminol in bicarbonate was approx. 10(-3). Chemiluminescence was superoxide dismutase-inhibitable, indicating that O2.- was a key intermediate for chemiexcitation. O2.- appears to be formed secondarily to the reaction of a bicarbonate-peroxynitrite complex with luminol, yielding luminol radical and O2.-. Luminol radical reacts with O2.- to form the unstable luminol endoperoxide, which follows the light-emitting pathway. Neither .NO nor O2.- alone were capable of directly inducing significant luminol chemiluminescence in our assay systems. These results suggest that ONOO- can be a critical unrecognized mediator of cell-derived luminol chemiluminescence reported in previous studies. In addition, it is shown that bicarbonate can participate in secondary oxidation reactions after reacting with ONOO-.
Insulin-Like Growth Factor-I at Physiological Concentrations Is a Potent Inhibitor of Insulin Secretion* (1990)

Insulin-like growth factors I and II (IGF-I and IGF-II) are thought to primarily regulate the growth and development of a number of tissues. However, it has recently been observed that when IGF-I is infused into man and animals, plasma insulin levels fall, raising the possibility that IGF-I may also be an inhibitor of insulin secretion. This study used the in vitro perfused rat pancreas and recombinant human IGF-I and IGF-II to determine if either of these peptides affected insulin and/or glucagon secretion from normal rats. IGF-I given with 7.8 mM glucose suppressed insulin secretion by as much as 65%, with the half-maximal effect occurring at less than 10 ng/ml. Glucose-induced insulin secretion (7.8 mM glucose) and arginine-induced insulin secretion (10 mM arginine plus 7.8 mM glucose) were inhibited equally (40%) by 2 ng/ml IGF-I. Insulin secretion returned to normal within minutes of stopping IGF-I. IGF-II (200 ng/ml) also suppressed insulin release, but the effect was less pronounced than for IGF-I and was present at 16.7 mM glucose, but not at 7.8 mM glucose. In contrast to the effects on insulin release, neither peptide altered glucagon secretion. We conclude from these results that 1) IGF-I at physiological concentrations is a potent inhibitor of both glucose- and arginine-induced insulin secretion; 2) the magnitude of the inhibition depends on the background glucose concentration; and 3) the inhibition fully reverses when IGF-I is stopped. These results support an in vivo effect of IGF-I to modulate insulin output.
Bcl-2/Adenovirus E1B 19 kDa Interacting Protein-3 Knockdown Enables Growth of Breast Cancer Metastases in the Lung, Liver, and Bone (2005)

The mouse breast cancer cell lines 4T1, 4T07, and 67NR are highly tumorigenic but vary in metastatic potential: 4T1 widely disseminates, resulting in secondary tumors in the lung, liver, bone, and brain; 4T07 spreads to the lung and liver but is unable to establish metastatic nodules; 67NR is unable to metastasize. The Bcl-2/adenovirus E1B 19 kDa interacting protein-3 (Bnip-3) was recently shown to be absent after hypoxia in pancreatic cancer cell lines whereas its overexpression restored hypoxia-induced cell death. We found that Bnip-3 expression increased after 6 hours of hypoxia in all cell lines tested but was highest in the nonmetastatic 67NR cells and lowest in the highly metastatic 4T1 cells. Hypoxia-induced expression of Bnip-3 in the disseminating but nonmetastatic 4T07 cells was intermediate compared with 4T1 and 67NR cells. Cleaved caspase-3, a key downstream effector of cell death, increased after 6 hours of hypoxia in the 67NR and 4T07 cells by 1.9- and 2.5-fold, respectively. Conversely, cleaved caspase-3 decreased by 45% in the highly metastatic 4T1 cells after hypoxia. Small interfering RNA oligonucleotides targeting endogenous Bnip-3 blocked cell death and increased clonigenic survival after hypoxic challenge in vitro and increased primary tumor size and enabled metastasis to the lung, liver, and sternum of mice inoculated with 4T07 cells in vivo. These data inversely correlate the hypoxia-induced expression of the cell death protein Bnip-3 to metastatic potential and suggest that loss of Bnip-3 expression is critical for malignant and metastatic evasion of hypoxia-induced cell death.
Two nuclear localization signals are required for nuclear translocation of nuclear factor 1‐A (2000)

Nuclear factor 1 (NF1) proteins are encoded by at least four genes (NF1-A, B, C, X). Although DNA-binding and the transcription regulation domains of these proteins are well characterized, the nuclear localization signals (NLSs) are still unknown in all NF1s. We have identified two NLSs in NF1-A, and both are required for full translocation to the nucleus, although one of them itself has a partial translocation ability. These two NLSs are conserved in all four NF1s. Interestingly, three isoforms of NF1-A (NF1-A1, A2, A4) have two NLSs and translocate completely to the nucleus. In contrast, NF1-A3 lacks the second NLS and partially stays in the cytoplasm. Since NF1s construct homodimer and heterodimer, these findings indicate the differential regulations of the NF1 translocation.