gebhart/patrepeval huggingface dataset:
Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. (1998)

The folate antagonist methotrexate (MTX) is extensively used in graft-versus-host disease, rheumatoid arthritis, and other chronic inflammatory disorders. In addition to its antiinflammatory activity associated with increased release of adenosine, MTX exerts antiproliferative properties by inhibition of dihydrofolate reductase and other folate-dependent enzymes. However, the mechanisms of immunosuppressive properties associated with low-dose MTX treatments are still elusive. We report here that MTX (0.1-10 microM) induces apoptosis of in vitro activated T cells from human peripheral blood. PBL exposed to MTX for 8 h, then activated in drug-free medium, underwent apoptosis, which was completely abrogated by addition of folinic acid or thymidine. Apoptosis of activated T cells did not require interaction between CD95 (Fas, APO-1) and its ligand, and adenosine release accounted for only a small part of this MTX activity. Apoptosis required progression of activated T cells to the S phase of the cell cycle, as it was prevented by drugs or antibodies that interfere with IL-2 synthesis or signaling pathways. MTX achieved clonal deletion of activated T cells in mixed lymphocyte reactions. Finally, in vitro activation of PBL taken from rheumatoid arthritis patients after MTX injection resulted in apoptosis. Altogether, the data demonstrate that MTX can selectively delete activated peripheral blood T cells by a CD95-independent pathway. This property could be used as a new pharmacological end point to optimize dosage and timing of MTX administration. It may account for the immunosuppressive effects of low-dose MTX treatments.
Cover Picture: Eur. J. Immunol. 10/08 (2008)

Abstract The cover image depicts multi‐nucleated osteoclasts stained for tartrate‐resistant alkaline phosphatase (maroon colour) after in vitro differentiation from bone marrow myeloid cells. The image was taken from the article of Chen et al . ( pp . 2845–2854), in which the authors demonstrate that the proinflammatory IL‐12 family cytokine, IL‐23, up‐regulates RANK expression in myeloid precursor cells and sensitizes cells for commitment to the osteoclast lineage.
Structural insights into triple-helical collagen cleavage by matrix metalloproteinase 1 (2012)

Collagenases of the matrix metalloproteinase (MMP) family play major roles in morphogenesis, tissue repair, and human diseases, but how they recognize and cleave the collagen triple helix is not fully understood. Here, we report temperature-dependent binding of a catalytically inactive MMP-1 mutant (E200A) to collagen through the cooperative action of its catalytic and hemopexin domains. Contact between the two molecules was mapped by screening the Collagen Toolkit peptide library and by hydrogen/deuterium exchange. The crystal structure of MMP-1(E200A) bound to a triple-helical collagen peptide revealed extensive interactions of the 115-Å-long triple helix with both MMP-1 domains. An exosite in the hemopexin domain, which binds the leucine 10 residues C-terminal to the scissile bond, is critical for collagenolysis and represents a unique target for inhibitor development. The scissile bond is not correctly positioned for hydrolysis in the crystallized complex. A productive binding mode is readily modeled, without altering the MMP-1 structure or the exosite interactions, by axial rotation of the collagen homotrimer. Interdomain flexing of the enzyme and a localized excursion of the collagen chain closest to the active site, facilitated by thermal loosening of the substrate, may lead to the first transition state of collagenolysis.
FixMatch: Simplifying Semi-Supervised Learning with Consistency and Confidence (2020)

Semi-supervised learning (SSL) provides an effective means of leveraging unlabeled data to improve a model's performance. In this paper, we demonstrate the power of a simple combination of two common SSL methods: consistency regularization and pseudo-labeling. Our algorithm, FixMatch, first generates pseudo-labels using the model's predictions on weakly-augmented unlabeled images. For a given image, the pseudo-label is only retained if the model produces a high-confidence prediction. The model is then trained to predict the pseudo-label when fed a strongly-augmented version of the same image. Despite its simplicity, we show that FixMatch achieves state-of-the-art performance across a variety of standard semi-supervised learning benchmarks, including 94.93% accuracy on CIFAR-10 with 250 labels and 88.61% accuracy with 40 -- just 4 labels per class. Since FixMatch bears many similarities to existing SSL methods that achieve worse performance, we carry out an extensive ablation study to tease apart the experimental factors that are most important to FixMatch's success. We make our code available at https://github.com/google-research/fixmatch.
T cell factor (interleukin 2) allows in vivo induction of T helper cells against heterologous erythrocytes in athymic (nu/nu) mice (1980)

Mice carrying the nude mutation (nu/nu) lack a functioning thymus and do not contain detectable levels of immunocompetent T cells. We now report that nu/nu mice to have lymphocytes which can be activated in vivo by heterologous erythrocytes and a Lyt-1 T cell-derived factor (interleukin 2) to generate T helper cells. Thus, a lymphokine is described which is able to restore in vivo T helper cell immunocompetence of nu/nu mice. The data may suggest that nu/nu mice contain a low number of T lymphocytes influenced by the cystic remnant of the nu/nu thymus anlage. Alternatively, the data imply that interleukin 2 circumvents the requirement of a thymus during ontogeny of T lymphocytes.
Reslizumab, a humanized anti-IL-5 mAb for the treatment of eosinophil-mediated inflammatory conditions. (2009)

Eosinophils are pro-inflammatory cells that make a major contribution to allergic diseases affecting the upper and lower airways, skin and gastrointestinal tract. IL-5 is central to eosinophil maturation and release from the bone marrow, and to the subsequent accumulation, activation and persistence of eosinophils in the tissues. Reslizumab from Ception Therapeutics Inc is a humanized mAb with potent IL-5-neutralizing effects. The agent inhibited eosinophilia in several animal models; reductions in airway hyperactivity and bronchoconstriction were also observed. Clinical trials for reslizumab have been completed in a small number of patients with asthma, nasal polyposis, hypereosinophilic syndrome (HES) and eosinophil gastroenteritis (EG). Eosinophil depletion was observed in all trials, but clinical responses were often limited, particularly in patients with asthma; furthermore, some patients exhibited rebound of disease to levels greater than baseline. At the time of publication, phase II/III and phase III trials were ongoing in patients with eosinophilic esophagitis (EE), and a phase II trial was ongoing in patients with asthma. Reslizumab is a potentially efficacious and well-tolerated treatment for EG, EE, HES and eosinophilic polyposis, although more trials are required to understand the underlying mechanism of disease rebound. However, the rarity of conditions such as HES, EE and EG makes the conduct of such trials difficult.
Sequence Analysis of Insecticidal Genes from Xenorhabdus nematophilus PMFI296 (2001)

Three strains of Xenorhabdus nematophilus showed insecticidal activity when fed to Pieris brassicae (cabbage white butterfly) larvae. From one of these strains (X. nematophilus PMFI296) a cosmid genome library was prepared in Escherichia coli and screened for oral insecticidal activity. Two overlapping cosmid clones were shown to encode insecticidal proteins, which had activity when expressed in E. coli (50% lethal concentration [LC(50)] of 2 to 6 microg of total protein/g of diet). The complete sequence of one cosmid (cHRIM1) was obtained. On cHRIM1, five genes (xptA1, -A2, -B1, -C1, and -D1) showed homology with up to 49% identity to insecticidal toxins identified in Photorhabdus luminescens, and also a smaller gene (chi) showed homology to a putative chitinase gene (38% identity). Transposon mutagenesis of the cosmid insert indicated that the genes xptA2, xptD1, and chi were not important for the expression of insecticidal activity toward P. brassicae. One gene (xptA1) was found to be central for the expression of activity, and the genes xptB1 and xptC1 were needed for full activity. The location of these genes together on the chromosome and therefore present on a single cosmid insert probably accounted for the detection of insecticidal activity in this E. coli clone. Although multiple genes may be needed for full activity, E. coli cells expressing the xptA1 gene from the bacteriophage lambda P(L) promoter were shown to have insecticidal activity (LC(50) of 112 microg of total protein/g of diet). This is contrary to the toxin genes identified in P. luminescens, which were not insecticidal when expressed individually in E. coli. High-level gene expression and the use of a sensitive insect may have aided in the detection of insecticidal activity in the E. coli clone expressing xptA1. The location of these toxin genes and the chitinase gene and the presence of mobile elements (insertion sequence) and tRNA genes on cHRIM1 indicates that this region of DNA represents a pathogenicity island on the genome of X. nematophilus PMFI296.
Preparing for the Next Pandemic (2005)

The fragile and limited production capacity of our 1950s egg-based technology for producing influenza vaccine and the lack of a national commitment to universal annual influenza vaccination mean that influenza epidemics will continue to present a substantial public health challenge. Dr. Michael Osterholm asks, So how can we prepare?
Functional Properties of Deamidated Oat Protein Isolates (1987)

ABSTRACT Oat protein isolates were deamidated by mild acid hydrolysis. Amino acid analysis and gel filtraiton chromatography showed no significant cleavage of peptide linkages although the aggregated and oligomeric oat proteins were extensively dissociated. Deamidation led to marked improvement in solubility, emulsifying properties and water and fat binding capacities. The pH for heat‐induced gelation was lowered by deamidation, and a firm, elastic gel was produced by mixing egg white with deamidated oat isolates.
Lenalidomide in Nonmetastatic Biochemically Relapsed Prostate Cancer: Results of a Phase I/II Double-Blinded, Randomized Study (2010)

Lenalidomide has acceptable toxicity and is associated with long-term disease stabilization and PSA declines. Randomized studies evaluating conventional clinical disease end points in this patient population are planned.
Alternative splicing of human VCAM-1 in activated vascular endothelium. (1991)

Vascular cell adhesion molecule 1 (VCAM-1)/inducible cell adhesion molecule 110 is a mononuclear leukocyte-selective adhesion molecule, expressed on vascular endothelium following activation by certain cytokines or endotoxin. This inducible transmembrane protein and member of the immunoglobulin gene superfamily was previously reported to contain six immunoglobulinlike domains. Using the polymerase chain reaction, a VCAM-1 cDNA was obtained from mRNA of interleukin-1 (IL-1)-treated cultured human umbilical vein endothelial cells (HUVEC). The cDNA clone contained an additional 276 base-pair (bp) domain, located between domains 3 and 4. This new domain is most homologous to the existing N-terminal domain (domain 1). The internal 276-bp region is encoded by a single exon of the human VCAM-1 gene, indicating that the two forms of mRNA arise by alternative splicing. Both forms of VCAM-1 mRNA were detected by polymerase chain reaction in IL-1-stimulated HUVEC, although the seven-domain form appeared predominant. On the surface of HUVEC only a 110-kd polypeptide, consistent with the seven-immunoglobulinlike domain form of VCAM-1, was detectable by immunoprecipitation. Alternative splicing of the VCAM-1 gene in cytokine-activated endothelium may generate functionally distinct cell-surface adhesion molecules.
Twofish : A 128-bit block cipher (1998)

Twofish is a 128-bit block cipher that accepts a variable-length key up to 256 bits. The cipher is a 16-round Feistel network with a bijective F function made up of four key-dependent 8-by-8-bit S-boxes, a fixed 4-by-4 maximum distance separable matrix over GF(28), a pseudo-Hadamard transform, bitwise rotations, and a carefully designed key schedule. A fully optimized implementation of Twofish encrypts on a Pentium Pro at 17.8 clock cycles per byte, and an 8-bit smart card implementation encrypts at 1660 clock cycles per byte. Twofish can be implemented in hardware in 14000 gates. The design of both the round function and the key schedule permits a wide variety of tradeoffs between speed, software size, key setup time, gate count, and memory. We have extensively cryptanalyzed Twofish; our best attack
The enzymes of β-lactam biosynthesis (2012)

The β-lactam antibiotics and related β-lactamase inhibitors are amongst the most important small molecules in clinical use. Most, but not all, β-lactams including penicillins, cephalosporins, and clavulanic acid are produced via fermentation or via modification of fermented intermediates, with important exceptions being the carbapenems and aztreonam. The desire for more efficient routes to existing antibiotics and for access to new and synthetically challenging ones stimulates continued interest in β-lactam biosynthesis. We review knowledge of the pathways leading to β-lactam antibiotics focusing on the mechanisms, structures and biocatalytic applications of the enzymes involved.
Amplified gene expression in CD59-transfected Chinese hamster ovary cells confers protection against the membrane attack complex of human complement (1991)

Protection against the pore-forming activity of the human C5b-9 proteins was conferred on a nonprimate cell by transfection with cDNA encoding the human complement regulatory protein CD59. CD59 was stably expressed in Chinese hamster ovary cells using the pFRSV mammalian expression vector. After cloning and selection, the transfected cells were maintained in media containing various concentrations of methotrexate, which induced surface expression of up to 4.2 x 10(6) molecules of CD59/cell. Phosphatidylinositol-specific phospholipase C removed greater than 95% of surface-expressed CD59 antigen, confirming that recombinant CD59 was tethered to the Chinese hamster ovary plasma membrane by a lipid anchor. The recombinant protein exhibited an apparent molecular mass of 21-24 kDa (versus 18-21 kDa for human erythrocyte CD59). After N-glycanase digestion, recombinant and erythrocyte CD59 comigrated with apparent molecular masses of 12-14 kDa, suggesting altered structure of asparagine-linked carbohydrate in recombinant versus erythrocyte CD59. The function of the recombinant protein was evaluated by changes in the sensitivity of the CD59 transfectants to the pore-forming activity of human C5b-9. Induction of cell-surface expression of CD59 antigen inhibited C5b-9 pore formation in a dose-dependent fashion. CD59 transfectants expressing greater than or equal to 1.2 x 10(6) molecules of CD59/cell were completely resistant to human serum complement. By contrast, CD59 transfectants remained sensitive to the pore-forming activity of guinea pig C8 and C9 (bound to human C5b67). Functionally blocking antibody against erythrocyte CD59 abolished the human complement resistance observed for the CD59-transfected Chinese hamster ovary cells. These results confirm that the C5b-9 inhibitory function of the human erythrocyte membrane is provided by CD59 and suggest that the gene for this protein can be expressed in xenotypic cells to confer protection against human serum complement.
A head-mounted three dimensional display (1968)

The fundamental idea behind the three-dimensional display is to present the user with a perspective image which changes as he moves. The retinal image of the real objects which we see is, after all, only two-dimensional. Thus if we can place suitable two-dimensional images on the observer's retinas, we can create the illusion that he is seeing a three-dimensional object. Although stereo presentation is important to the three-dimensional illusion, it is less important than the change that takes place in the image when the observer moves his head. The image presented by the three-dimensional display must change in exactly the way that the image of a real object would change for similar motions of the user's head. Psychologists have long known that moving perspective images appear strikingly three-dimensional even without stereo presentation; the three-dimensional display described in this paper depends heavily on this "kinetic depth effect."
Die Kristallstrukturen von α‐Na2S2 und K2S2, β‐Na2S2 und Na2Se2 (1962)

Abstract α‐Na 2 S 2 (a = 7,629 Å; c = 5,394 Å) und K 2 S 2 (a = 8,49 Å; c = 5,84 Å) kristallisieren hexagonal in der Raumgruppe D —P 6 2m mit 3 Formeleinheiten pro Zelle. Sie sind isotyp mit Na 2 O 2 . β‐Na 2 S 2 (a = 4,494 Å; c = 10,228 Å) und Na 2 Se 2 (a = 4,685 Å; c = 10,53 Å) kristallisieren hexagonal in der Raumgruppe D —P6 3 /mmc mit 2 Formeleinheiten pro Zelle. Sie sind isotyp mit Li 2 O 2 . Charakteristisch für alle vier Kristallstrukturen ist das Auftreten von S ‐Hanteln, die parallel der c‐Achse angeordnet sind. Der SS‐(SeSe)‐Abstand beträgt 2,13 Å (2,38 Å). Die Strukturuntersuchungen wurden mit Hilfe von Drehkristall‐ und Pulveraufnahmen durchgeführt.
Effectiveness of Enteric-Coated Preparations on Nutritional Parameters in Cystic Fibrosis (1988)

To evaluate the effectiveness of enteric-coated pancreatic enzyme supplements in comparison to conventional preparations of ingested enzyme on growth and nutritional parameters of patients with cystic fibrosis, we conducted a long-term study involving 40 patients. The data reproduced here were recorded after 6 months of therapy with powder-containing capsules or with enteric-coated products. Fat absorption was estimated by measurement of steatorrhoea with the steatocrit method. All parameters studied improved after enteric-coated pancreatic enzyme therapy, with a statistically significant increase in weight, cholesterol and haemoglobin values. Furthermore, the number of patients with positive steatocrit test was lower after therapy with enteric-coated enzyme supplementation. These findings suggest that the enteric-coated product not only reduces steatorrhoea, but above all improves the nutritional parameters and growth of patients affected by cystic fibrosis.
Biochemical evidence for the autophosphorylation and transphosphorylation of transforming growth factor beta receptor kinases. (1995)

Transforming growth factor beta (TGF-beta) signals through a receptor complex containing the type I (TGF-beta RI) and type II (TGF-beta RII) receptors. We describe here biochemical studies on early events in the TGF-beta signaling pathways. TGF-beta RII is highly phosphorylated when expressed alone in COS-1 cells; its autophosphorylation occurs via an intramolecular (cis) mechanism that is independent of ligand binding. TGF-beta RI is also highly phosphorylated when expressed alone in COS-1 cells. Both wild-type TGF-beta RI and a kinase-deficient mutant thereof are transphosphorylated by the coexpressed TGF-beta RII kinase in a ligand-independent fashion in these cells. We propose that the association of TGF-beta RI and TGF-beta RII, induced by ligand binding or over-expression, leads to transphosphorylation of the TGF-beta RI by the TGF-beta RII kinase. This represents a mechanism of activation of receptors distinct from that of tyrosine kinase receptors and may apply to other serine/threonine kinase receptors.
Amino acid recognition by Venus flytrap domains is encoded in an 8‐residue motif (2005)

A motif foramino acid recognition by proteins or domains of the periplasmic binding protein-like I superfamily has been identified. An initial pattern of 5 residues was based on a multiple sequence alignment of selected proteins of that fold family and on common structural features observed in the crystal structure of some members of the family [leucine isoleucine valine binding protein (LIVBP), leucine binding protein (LBP), and metabotropic glutamate receptor type 1 (mGlu1R) amino terminal domain)]. This pattern was used against the PIR-NREF sequence database and further refined to retrieve all sequences of proteins that belong to the family and eliminate those that do not belong to it. A motif of 8 residues was finally selected to build up the general signature. A total of 232 sequences were retrieved. They were found to belong to only three families of proteins: bacterial periplasmic binding proteins (PBP, 71 sequences), family 3 (or C) of G-protein coupled receptor (GPCR) (146 sequences), and plant putative ionotropic glutamate receptors (iGluR, 15 sequences). PBPs are known to adopt a bilobate structure also named Venus flytrap domain, or LIVBP domain in the present case. Family 3/C GPCRs are also known to hold such a domain. However, for plant iGluRs, it was previously detected by classical similarity searches but not specifically described. Thus plant iGluRs carry two Venus flytrap domains, one that binds glutamate and an additional one that would be a modulatory LIVBP domain. In some cases, the modulator binding to that domain would be an amino acid.
Upstream Stimulatory Factor Binding to the E-box at −65 Is Required for Insulin Regulation of the Fatty Acid Synthase Promoter (1997)

Fatty acid synthase (FAS) plays a central role in de novo lipogenesis in mammals. We have shown that FAS transcription rate is induced dramatically when fasted animals are refed with a high carbohydrate diet or when streptozotocin-diabetic mice are given insulin. We also reported that FAS gene transcription was up-regulated by insulin through the proximal promoter region from -71 to -50 and that upstream stimulatory factors (USFs), including USF1 and USF2, interact with this region in vitro. In the present study, by using site-directed mutagenesis of the -71/-50 region and correlating functional assays of the mutated promoter with USF binding activities, we demonstrate that the -65/-60 E-box motif (5'-CATGTG-3') is functionally required for insulin regulation and that USFs are in vivo components of the insulin response complex. Mutation of the -65/-60 E-box sequence abolished insulin response in both transiently and stably transfected 3T3-L1 adipocytes in the -2. 1 kb promoter context, which contains all the necessary regulatory elements of the promoter based on our previous transgenic mice studies, and in the minimal -67 promoter context. Gel mobility shift assays demonstrated that USFs can no longer bind to the -71/-50 promoter region when the E-box is mutated. Cotransfection of USF1 and USF2 expression vectors with the FAS promoter-luciferase reporter constructs increased insulin-stimulated FAS promoter activity. Moreover, cotransfection of dominant negative USF1 and USF2 mutants lacking the DNA binding domain inhibited the insulin stimulation of the FAS promoter activity. On the other hand, site-directed mutagenesis of the -65/-60 E-box surrounding sequences within the overlapped tandem copies of sterol regulatory element-binding protein (SREBP) binding sites prevented SREBP from binding to -71/-50 promoter region in vitro but had no effect on insulin regulation of the FAS promoter in vivo. When rat liver nuclear extracts were used in gel mobility shift assays, only USF-containing protein-DNA complexes that can be supershifted by specific USF antibodies were observed. These results demonstrate that upstream stimulatory factor binding to the E-box at -65 is required for insulin regulation of the fatty acid synthase promoter.