gebhart/patrepeval huggingface dataset:
Pharmacokinetics and enhancement patterns of macromolecular MR contrast agents with various sizes of polyamidoamine dendrimer cores (2001)

Four macromolecular contrast agents are synthesized to visualize small vessels by MRI using generation-3 (G3D), -4 (G4D), -5 (G5D), and -6 (G6D) polyamidoamine dendrimers conjugated to chelated gadolinium (Gd). The pharmacokinetics, enhancement patterns, and the ability of these constructs to visualize fine vessels is evaluated by dynamic MRI in relationship to their size. Gd-G6D and -G5D exhibit a prolonged high vascular (ventricular) signal intensity (SI) with high ventricle-to-organ SI ratios. The initial high vascular SI with Gd-G4D decreases to a value as low as that obtained with Gd-G3D and Gd-dimeglumine-diethylenetriaminepentaacetic acid (Gd-DTPA). Gd-G5D, -G4D, and -G3D show high renal SIs, and Gd-DTPA prominently enhances the skin. Gd-G6D and -G5D present fine vasculature significantly more clearly than Gd-G3D and -DTPA (P < 0.005). As the molecular size increases, the excretion of the 153Gd-conjugates is retarded. In conclusion, Gd-G6D and -G5D are retained in the blood and present fine vessels with high quality and detail, and should be adequate for visualizing small tumor vasculature.
Crystal structure of a peptidoglycan glycosyltransferase suggests a model for processive glycan chain synthesis (2007)

Peptidoglycan is an essential polymer that forms a protective shell around bacterial cell membranes. Peptidoglycan biosynthesis is the target of many clinically used antibiotics, including the beta-lactams, imipenems, cephalosporins, and glycopeptides. Resistance to these and other antibiotics has prompted interest in an atomic-level understanding of the enzymes that make peptidoglycan. Representative structures have been reported for most of the enzymes in the pathway. Until now, however, there have been no structures of any peptidoglycan glycosyltransferases (also known as transglycosylases), which catalyze formation of the carbohydrate chains of peptidoglycan from disaccharide subunits on the bacterial cell surface. We report here the 2.1-A crystal structure of the peptidoglycan glycosyltransferase (PGT) domain of Aquifex aeolicus PBP1A. The structure has a different fold from all other glycosyltransferase structures reported to date, but it bears some resemblance to lambda-lysozyme, an enzyme that degrades the carbohydrate chains of peptidoglycan. An analysis of the structure, combined with biochemical information showing that these enzymes are processive, suggests a model for glycan chain polymerization.
Immunoglobulin Somatic Hypermutation (2007)

The immunoglobulin (Ig) repertoire achieves functional diversification through several somatic alterations of the Ig locus. One of these processes, somatic hypermutation (SHM), deposits point mutations into the variable region of the Ig gene to generate higher-affinity variants. Activation-induced cytidine deaminase (AID) converts cytidine to uridine to initiate the hypermutation process. Error-prone versions of DNA repair are believed to then process these lesions into a diverse spectrum of point mutations. We review the current understanding of the molecular mechanisms and regulation of SHM, and also discuss emerging ideas which merit further exploration.
RANTES Activates Jak2 and Jak3 to Regulate Engagement of Multiple Signaling Pathways in T Cells (2001)

The chemokine RANTES (regulated on activation normal T cell expressed and secreted) and its cognate receptor CC chemokine receptor 5 (CCR5) have been implicated in regulating immune cell function. Previously we reported that in T cells, RANTES activation of CCR5 results in Stat1 and Stat3 phosphorylation-activation, leading to Stat1:1 and Stat1:3 dimers that exhibit DNA binding activity and the transcriptional induction of a Stat-inducible gene, c-fos. Given that RANTES and CCR5 have been implicated in T cell activation, we have studied RANTES-induced signaling events in a CCR5-expressing T cell line, PM1. RANTES treatment of PM1 T cells results in the rapid phosphorylation-activation of CCR5, Jak2, and Jak3. RANTES-inducible Jak phosphorylation is insensitive to pertussis toxin inhibition, indicating that RANTES-CCR5-mediated tyrosine phosphorylation events are not coupled directly to Galpha(i) protein-mediated events. In addition to Jaks, several other proteins are rapidly phosphorylated on tyrosine residues in a RANTES-dependent manner, including the Src kinase p56(lck), which associates with Jak3. Additionally our data confirm that the amino-terminally modified RANTES proteins, aminooxypentane-RANTES and Met-RANTES, are agonists for CCR5 and induce early tyrosine phosphorylation events that are indistinguishable from those inducible by RANTES with similar kinetics. Our data also demonstrate that RANTES activates the p38 mitogen-activated protein (MAP) kinase pathway. This is evidenced by the rapid RANTES-dependent phosphorylation and activation of p38 MAP kinase as well as the activation of the downstream effector of p38, MAP kinase-activated protein (MAPKAP) kinase-2. Pharmacological inhibition of RANTES-dependent p38 MAP kinase activation blocks MAPKAP kinase-2 activity. Thus, activation of Jak kinases and p38 MAP kinase by RANTES regulates the engagement of multiple signaling pathways.
Primary structure and distribution of a novel ryanodine receptor/calcium release channel from rabbit brain (1992)

The complete amino acid sequence of a novel ryanodine receptor/calcium release channel from rabbit brain has been deduced by cloning and sequence analysis of the cDNA. This protein is composed of 4872 amino acids and shares characteristic structural features with the skeletal muscle and cardiac ryanodine receptors. RNA blot hybridization analysis shows that the brain ryanodine receptor is abundantly expressed in corpus striatum, thalamus and hippocampus, whereas the cardiac ryanodine receptor is more uniformly expressed in the brain. The brain ryanodine receptor gene is transcribed also in smooth muscle.
Shear-Dependent Boundary Slip in an Aqueous Newtonian Liquid (2001)

We report direct measurements of hydrodynamic drainage forces, which show clear evidence of boundary slip in a Newtonian liquid. The degree of boundary slip is found to be a function of the liquid viscosity and the shear rate, as characterized by the slip length, and is up to approximately 20 nm. This has implications for confined biological systems, the permeability of microporous media, and for the lubrication of nanomachines, and will be important in the microcontrol of liquid flow. We also show that current theories of slip do not adequately describe the experimental data.
Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint (2001)

These results indicate that the ELR-containing chemokines IL-8 and ENA-78 are important contributors to the angiogenic activity found in the inflamed RA joint. It is possible that efforts aimed at down-regulating these chemokines offer a novel targeted therapy for the treatment of RA.
Androgen receptor (AR) level in the prostatectomy specimen predicts time to disease progression post androgen suppression therapy (2007)

5065 Background: The androgen receptor (AR) plays an important role in the initiation and growth of prostate cancer and its subsequent response to hormone therapy. Previous analyses, including our own, have determined that elevated AR protein in the prostatectomy specimen is associated with progression of disease. We hypothesized that AR levels may also be predictive of response to androgen deprivation therapy (ADT) by evaluating time to castrate rise in PSA in patients treated with ADT at the time of a biochemical recurrence. By utilizing quantitative immunofluorescence (IF) and spectral imaging we evaluated AR content as an independent predictor of therapeutic outcome. Methods: 63 of 881 patients treated by radical prostatectomy had received ADT for a biochemical rise in PSA and or clinical progression of their disease. 32 of 63 patients had progressed post-ADT with a castrate rise in PSA. Tissue microarrays with triplicate patient cores were stained with a multiplex immunofluorescent assay (IF) which contained the nuclear marker DAPI, along with the following antibodies: Androgen Receptor (AR), Racemase (AMACR), CK18, HMWK and p63. IF images were acquired with spectral un-mixing employed to develop antibody-cell-specific gray scale images. Utilizing image analysis algorithms, quantitative features including intensity and area for selected antigens was generated. Results: Eleven IF antigen features were evaluated after feature selection and filtering using the concordance index with respect to outcome. A total of 5 features were statistically significant for predicting time to progression post therapy of which 2 features (AR intensity within AMACR (+) and (-) epithelial cells; p=0.0003 and p=0.0021, respectively) demonstrated that elevated levels of AR were associated with a shortened time to castrate rise in PSA post ADT. Clinical features alone were not found to be statistically significant with respect to predicting outcome. Conclusions: AR levels in the prostatectomy sample appears to be a useful indicator for determining therapeutic ADT response and potentially guiding future treatment decision and patient monitoring. No significant financial relationships to disclose.
Regulation of the Phosphorylation of Human Pharyngeal Cell Proteins by Group A Streptococcal Surface Dehydrogenase: Signal Transduction between Streptococci and Pharyngeal Cells (1997)

Whether cell-to-cell communication results when group A streptococci interact with their target cells is unknown. Here, we report that upon contact with cultured human pharyngeal cells, both whole streptococci and purified streptococcal surface dehydrogenase (SDH) activate pharyngeal cell protein tyrosine kinase as well as protein kinase C, thus regulating the phosphorylation of cellular proteins. SDH, a major surface protein of group A streptococci, has both glyceraldehyde-3-phosphate dehydrogenase and ADP-ribosylating enzyme activities that may relate to early stages of streptococcal infection. Intact streptococci and purified SDH induce a similar protein phosphorylation pattern with the de novo tyrosine phosphorylation of a 17-kD protein found in the membrane/particulate fraction of the pharyngeal cells. However, this phosphorylation required the presence of cytosolic components. NH2-terminal amino acid sequence analysis identified the 17-kD protein as nuclear core histone H3. Both phosphotyrosine and phosphoserine-specific monoclonal antibodies reacted with the 17-kD protein by Western blot, suggesting that the binding of SDH to these pharyngeal cells elicits a novel signaling pathway that ultimately leads to activation of histone H3-specific kinases. Genistein-inhibitable phosphorylation of histone H3 indicates that tyrosine kinase plays a key role in this event. Treatment of pharyngeal cells with protein kinase inhibitors such as genistein and staurosporine significantly inhibited streptococcal invasion of pharyngeal cells. Therefore, these data indicated that streptococci/SDH-mediated phosphorylation plays a critical role in bacterial entry into the host cell. To identify the membrane receptor that elicits these signaling events, we found that SDH bound specifically to 30- and 32-kD membrane proteins in a direct ligand-binding assay. These findings clearly suggest that SDH plays an important role in cellular communication between streptococci and pharyngeal cells that may be important in host cell gene transcription, and hence in the pathogenesis of streptococcal infection.
Photoaffinity Labeling of the Lutropin Receptor with Synthetic Peptide for Carboxyl Terminus of the Human Choriogonadotropin γ Subunit (1996)

Human choriogonadotropin (hCG) consists of an alpha subunit and a beta subunit. The existing evidence from various studies using truncation, substitution, synthetic hormone peptides, and hCG crystals suggests that the C-terminal region of the alpha subunit contacts the luteinizing hormone/choriogonoadotropin (LH/CG) receptor and is involved in receptor activation. Despite a deluge of the speculation and the important role of the alpha C-terminal region, direct evidence for its interaction with the receptor has been elusive. Because of the significant biological activity, it is imperative to prove the interaction of the alpha C-terminal region. For this purpose, decamer peptides corresponding to the alpha subunit sequence from His83 to Ser92 (alpha 83-92) were derivatized with the N-hydroxysuccinimide ester of 4-azidobenzoylglycine (ABG) and radioiodinated. The resulting ABG-125I-alpha 83-92 was capable of binding and activating the LH/CG receptor. Furthermore, UV-sensitive ABG-125I-alpha 83-92 exclusively photoaffinity-labeled an approximately of 86-kDa molecule. This labeled molecule was shown to be the LH/CG receptor by various methods including immunoprecipitation by anti-LH/CG receptor antiserum. In addition, evidence is presented that the amino group of alpha Lys91 of alpha 83-92 is in such close proximity to a carboxyl group of the receptor that this pair is cross-linked to form an amide, a zero length cross-link. This low affinity contact of alpha 83-92 and the receptor is sufficient for receptor activation and is crucial for the full understanding of the mechanistics of the receptor activation steps.
Biocorrosion of magnesium alloys: a new principle in cardiovascular implant technology? (2003)

Vascular implants consisting of magnesium alloy degradable by biocorrosion seem to be a realistic alternative to permanent implants.
Helix pomatia Lectin, an Inducer of Drosophila Immune Response, Binds to Hemomucin, a Novel Surface Mucin (1996)

We describe the isolation and initial characterization of hemomucin, a novel Drosophila surface mucin that is likely to be involved in the induction of antibacterial effector molecules after binding a snail lectin (Helix pomatia A hemagglutinin). Two proteins of 100 and 220 kDa were purified from the membrane fraction of a Drosophila blood cell line using lectin columns. The two proteins are products of the same gene, as demonstrated by peptide sequencing. The corresponding cDNAs code for a product that contains an amino-terminal putative transmembrane domain, a domain related to the plant enzyme strictosidine synthase, and a mucin-like domain in the carboxyl-terminal part of the protein. The gene is expressed throughout development. In adult flies, high expression is found in hemocytes, in specialized regions of the gut, and in the ovary, where the protein is deposited onto the egg surface. In the gut, the mucin co-localizes with the peritrophic membrane. The cytogenetic location of the gene is on the third chromosome in the region 97F-98A.
Wrapping legacy COBOL programs behind an XML-interface (2002)

This paper describes the tools and techniques for encapsulating host COBOL programs with an XML interface. The legacy programs are divided into three classes - online programs, batch programs and subprograms. For each program type, a different wrapping technique and a different tool is employed. Online programs are transformed into data-driven subprograms which process an XML document. Batch programs are adapted to read and write XML documents. Subprograms are left unchanged, but their parameters are set from an XML document. By using XML to implement corporate portals, it has proven possible to reuse existing host programs within new intranet/Internet systems, thus reducing system development costs and development time by more than 60%.
How do CARs work? (2012)

Second-generation chimeric antigen receptors (CARs) are powerful tools to redirect antigen-specific T cells independently of HLA-restriction. Recent clinical studies evaluating CD19-targeted T cells in patients with B-cell malignancies demonstrate the potency of CAR-engineered T cells. With results from 28 subjects enrolled by five centers conducting studies in patients with chronic lymphocytic leukemia (CLL) or lymphoma, some insights into the parameters that determine T-cell function and clinical outcome of CAR-based approaches are emerging. These parameters involve CAR design, T-cell production methods, conditioning chemotherapy as well as patient selection. Here, we discuss the potential relevance of these findings and in particular the interplay between the adoptive transfer of T cells and pre-transfer patient conditioning.
Encoding a qubit in an oscillator (2001)

Quantum error-correcting codes are constructed that embed a finite-dimensional code space in the infinite-dimensional Hilbert space of a system described by continuous quantum variables. These codes exploit the noncommutative geometry of phase space to protect against errors that shift the values of the canonical variables q and p. In the setting of quantum optics, fault-tolerant universal quantum computation can be executed on the protected code subspace using linear optical operations, squeezing, homodyne detection, and photon counting; however, nonlinear mode coupling is required for the preparation of the encoded states. Finite-dimensional versions of these codes can be constructed that protect encoded quantum information against shifts in the amplitude or phase of a d-state system. Continuous-variable codes can be invoked to establish lower bounds on the quantum capacity of Gaussian quantum channels.
Dosage adjustment during long-term adalimumab treatment for Crohnʼs disease: Clinical efficacy and pharmacoeconomics (2010)

Of patients randomized to blinded EOW therapy, 19% moved to OL EOW therapy and 27% moved to OL weekly therapy for flares or lack of response versus baseline. Weekly therapy was associated with clear clinical benefits and a small cost increase.
(Aminoalkyl)indole Isothiocyanates as Potential Electrophilic Affinity Ligands for the Brain Cannabinoid Receptor (1996)

A series of (aminoalkyl)indole compounds, naphthalene analogs of pravadoline (1), has been shown to exhibit cannabinoid agonist activities such as antinociception in animals, inhibition of adenylate cyclase in brain membranes, and binding to the cannabinoid receptor. These pravadoline analogs were selected for the preparation of potential electrophilic affinity ligands based on the synthesis of isothiocyanate derivatives. One isothiocyanatonaphthalene derivative (8) displaced [3H]CP-55940 binding to a rat brain P2 membrane preparation with an IC50 of 690 nM, which was 10-fold less potent than the parent molecule (IC50 = 73 nM). Isothiocyanate substitution at various positions on the naphthalene moiety of the desmethyl analog 10 gave compounds that displaced [3H]CP-55940 with IC50 values between 400 and 1000 nM, compared with 46 nM for the parent compound 10. However, 6-isothiocyanato substitution on the indole ring of the desmethyl analog provided isothiocyanate 12 that displaced [3H]CP-55940 binding with an IC50 and 160 nM. After pretreatment of brain membranes with this high-affinity isothiocyanato ligand followed by washing out the ligand, the membranes were depleted of 90% of the cannabinoid receptor binding capacity. Loss of receptor binding capacity was half-maximal at 300 nM of the derivative under standard assay conditions. As a control, pretreatment with the parent compound at concentrations that were 20 times the Kd failed to alter subsequent binding activity. This study demonstrates that an isothiocyanato (aminoalkyl)-indole (12) can behave as an affinity ligand which binds irreversibly to the cannabinoid receptor in brain and which precludes subsequent binding of the cannabinoid ligand [3H]CP-55940.
Enhancement of graft-versus-tumor activity and graft-versus-host disease by pretransplant immunization of allogeneic bone marrow donors with a recipient-derived tumor cell vaccine. (1999)

Allogeneic bone marrow transplantation (BMT) can be accompanied by a beneficial T cell-mediated antitumor immune response known as graft-versus-tumor (GVT) activity. However, BMT donor T cells are not exposed to target antigens of GVT activity until transfer to the host, where tumor antigen presentation may be suboptimal. This study tested in a murine model the hypothesis that immunization of MHC-matched allogeneic donors with a recipient-derived tumor cell vaccine would substantially increase GVT activity and extend survival of BMT recipients with preexisting micrometastatic tumor. C3H.SW and C57BL/10 mice were immunized against a C57BL/6-derived fibrosarcoma or leukemia, and they were used as BMT donors. Recipients were H-2-matched, minor histocompatibility antigen-mismatched C57BL/6 mice with previously established micrometastatic tumors. Donor immunization led to a significant increase in GVT activity that was T cell dependent and cell dose dependent. In some settings, donor immunization also prolonged survival of recipients with preexisting micrometastatic tumors. However, donor immunization significantly increased the incidence of fatal graft-versus-host disease such that long-term survival was uncommon. In vitro cytotoxicity assays indicated that donor immunization induced both tumor-selective and alloreactive cytolytic T-cell populations. In vivo cross-protection assays showed that a substantial portion of the GVT effect was mediated by alloreactive cells not specific for the immunizing tumor. In conclusion, immunization of allogeneic BMT donors with a recipient-derived whole tumor cell vaccine substantially increases GVT activity but also exacerbates graft-versus-host disease.
An operator at -280 base pairs that is required for repression of araBAD operon promoter: addition of DNA helical turns between the operator and promoter cyclically hinders repression. (1984)

A site has been found that is required for repression of the Escherichia coli araBAD operon. This site was detected by the in vivo properties of deletion mutants. In vitro protection studies with DNase I and dimethylsulfate showed that araC protein can specifically bind in this area to nucleotides lying at position -265 to -294 with respect to the araBAD operon promoter (PBAD) transcription start point. The previously known sites of protein binding in the ara operon lie between +20 and -160. Since the properties of deletion strains show that all the sites required for araBAD induction lie between +20 and -110, the new site at -280 exerts its repressive action over an unusually large distance along the DNA. Insertions of -16, -8, 0, 5, 11, 15, 24, and 31 base pairs of DNA between the new site and PBAD were constructed. Repression was impaired in those cases in which half-integral turns of the DNA helix were introduced, but repression was nearly normal for the insertions of 0, +11, and +31 base pairs.
Predictive Markers of Honey Bee Colony Collapse (2012)

Across the Northern hemisphere, managed honey bee colonies, Apis mellifera, are currently affected by abrupt depopulation during winter and many factors are suspected to be involved, either alone or in combination. Parasites and pathogens are considered as principal actors, in particular the ectoparasitic mite Varroa destructor, associated viruses and the microsporidian Nosema ceranae. Here we used long term monitoring of colonies and screening for eleven disease agents and genes involved in bee immunity and physiology to identify predictive markers of honeybee colony losses during winter. The data show that DWV, Nosema ceranae, Varroa destructor and Vitellogenin can be predictive markers for winter colony losses, but their predictive power strongly depends on the season. In particular, the data support that V. destructor is a key player for losses, arguably in line with its specific impact on the health of individual bees and colonies.