gebhart/patrepeval huggingface dataset:
SB‐656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone‐induced airway inflammation in humans (2011)

SB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophil-predominant diseases.
Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires. (1996)

Immunological self-tolerance is ensured by eliminating or inhibiting self-reactive lymphocyte clones, creating physical or functional holes in the B- and T-lymphocyte antigen receptor repertoires. The nature and size of these gaps in our immune defenses must be balanced against the necessity of mounting rapid immune responses to an everchanging array of foreign pathogens. To achieve this balance, only a fraction of particularly hazardous self-reactive clones appears to be physically eliminated from the repertoire in a manner that fully prevents their recruitment into an antimicrobial immune response. Many self-reactive cells are retained with a variety of conditional and potentially flexible restraints: (i) their ability to be triggered by antigen is diminished by mechanisms that tune down signaling by their antigen receptors, (ii) their ability to carry out inflammatory effector functions can be inhibited, and (iii) their capacity to migrate and persist is constrained. This balance between tolerance and immunity can be shifted, altering susceptibility to autoimmune disease and to infection by genetic or environmental differences either in the way antigens are presented, in the tuning molecules that adjust triggering set points for lymphocyte responses to antigen, or in the effector molecules that eliminate, retain, or expand particular clones.
Molecular cloning and characterization of a novel orphan receptor (P2P) expressed in human pancreas that shows high structural homology to the P2U purinoceptor (1996)

Here we report the cloning of a gene encoding a new member of the superfamily of G protein-coupled receptors. The gene encodes a protein of 365 amino acids closely resembling two recently cloned nucleotide binding receptors, called P2U and P2Y purinoceptors (71% and 49% sequence identity within the transmembrane domains, respectively). Our studies show that this new putative purinoceptor (designated P2P) is encoded by an intronless single copy gene that is exclusively expressed in pancreas, in contrast to the P2U and the P2Y purinoceptors which are widely distributed throughout the periphery. The identification of a pancreas-specific human putative P2 purinoceptor makes it attractive to speculate that the reported actions of ADP/ATP analogues in pancreas on insulin secretion are mediated through this receptor.
Role of Residual Renal Function in Phosphate Control and Anemia Management in Chronic Hemodialysis Patients (2010)

This study suggests a strong relation between RRF and improved phosphate and anemia control in HD patients. Efforts to preserve RRF in HD patients could improve outcomes and should be encouraged.
Mapping of an NH--terminal Ligand Binding Site of the Insulin Receptor by Alanine Scanning Mutagenesis (1995)

Affinity labeling studies and mutational analyses have implicated the involvement of a predicted domain of the insulin receptor (L1, amino acids 1-119) in ligand binding. In order to obtain a higher resolution localization of this ligand binding site, we have performed alanine scanning mutagenesis of this domain. Alanine mutant cDNAs encoding a secreted recombinant insulin receptor extracellular domain were expressed transiently in adenovirus transformed human embryonic kidney cells and the affinity of the expressed receptor for insulin was determined. Mutation of 14 amino acids located in four discontinuous peptide segments to alanine was disruptive of insulin binding: Segment 1, amino acids 12-15; Segment 2, amino acids 34-44; Segment 3, amino acids 64-67; and Segment 4, amino acids 89-91. The quantitative contribution of the four segments to the free energy of insulin binding was 1 > 3 > 2 > 4. Of the 14 amino acids whose mutation compromised insulin binding, 3 are charged, 3 hydrophobic, 5 aromatic, and 3 are amides.
Role of extracellular calcium in anoxic injury of mammalian central white matter. (1990)

White matter (WM) of the mammalian brain is susceptible to anoxic injury, but little is known about the pathophysiology of this process. We studied the mechanisms of anoxic injury in WM using the isolated rat optic nerve, a typical central nervous system WM tract. Optic nerve function, measured as the area under the compound action potential, rapidly failed when exposed to anoxia and recovered to 28.5% of control after a standard 60-min period of anoxia. Irreversible anoxic injury was critically dependent on the molar concentration of extracellular calcium [( Ca2+]o); maintaining the tissue in Ca2(+)-free solution throughout the anoxic period resulted in 100% compound action potential recovery. Increasing perfusion [Ca2+] during anoxia from zero to 4 mM resulted in progressively less recovery. As the introduction of the Ca2(+)-free solution was progressively delayed with respect to the onset of anoxia, a graded decrease in recovery of function was observed, suggesting that in WM the deleterious effects of Ca2+ accumulate slowly during anoxia. At the time of reoxygenation, an additional stepwise increase in injury was observed that was also Ca2(+)-dependent. Mammalian WM, which is relatively resistant to anoxic injury compared with gray matter, is damaged by anoxia in a manner that appears to depend on the gradual accumulation of Ca2+ in a cytoplasmic compartment.
Toward Reliable Data Delivery for Highly Dynamic Mobile Ad Hoc Networks (2011)

This paper addresses the problem of delivering data packets for highly dynamic mobile ad hoc networks in a reliable and timely manner. Most existing ad hoc routing protocols are susceptible to node mobility, especially for large-scale networks. Driven by this issue, we propose an efficient Position-based Opportunistic Routing (POR) protocol which takes advantage of the stateless property of geographic routing and the broadcast nature of wireless medium. When a data packet is sent out, some of the neighbor nodes that have overheard the transmission will serve as forwarding candidates, and take turn to forward the packet if it is not relayed by the specific best forwarder within a certain period of time. By utilizing such in-the-air backup, communication is maintained without being interrupted. The additional latency incurred by local route recovery is greatly reduced and the duplicate relaying caused by packet reroute is also decreased. In the case of communication hole, a Virtual Destination-based Void Handling (VDVH) scheme is further proposed to work together with POR. Both theoretical analysis and simulation results show that POR achieves excellent performance even under high node mobility with acceptable overhead and the new void handling scheme also works well.
Fast Quantitative Assay of Sequence-Specific Endonuclease Activity Based on DNA Sequencer Technology (1992)

A quantitative assay of the sequence-specific endonuclease activity of Vsr DNA mismatch endonuclease is described. The procedure rests on fluorescently labelled oligonucleotide substrates and an automated DNA sequencer to determine amounts of both educt and product of the reaction; thus each individual measurement is internally standardized. The assay achieves high sample throughput by parallel measurement of multiple samples. Because of its capacity to produce and process large sets of experimental data, the system is particularly well suited for the determination of reaction kinetics. The procedure lends itself to further simplification by implementing software additions for direct peak integration. Obviously, the principle of the assay can be extended to the study of other enzymes, such as restriction endonucleases or sequence-specific proteases.
A Novel Mechanism of Transposon-Mediated Gene Activation (2009)

Transposable Insertion Sequences (IS elements) have been shown to provide various benefits to their hosts via gene activation or inactivation under stress conditions by appropriately inserting into specific chromosomal sites. Activation is usually due to derepression or introduction of a complete or partial promoter located within the element. Here we define a novel mechanism of gene activation by the transposon IS5 in Escherichia coli. The glycerol utilization operon, glpFK, that is silent in the absence of the cAMP-Crp complex, is activated by IS5 when inserted upstream of its promoter. High-level expression is nearly constitutive, only mildly dependent on glycerol, glucose, GlpR, and Crp, and allows growth at a rate similar to or more rapid than that of wild-type cells. Expression is from the glpFK promoter and dependent on (1) the DNA phase, (2) integration host factor (IHF), and (3) a short region at the 3' end of IS5 harboring a permanent bend and an IHF binding site. The lacZYA operon is also subject to such activation in the absence of Crp. Thus, we have defined a novel mechanism of gene activation involving transposon insertion that may be generally applicable to many organisms.
Inhibition of lipoprotein‐associated phospholipase A2 diminishes the death‐inducing effects of oxidised LDL on human monocyte‐macrophages (2001)

The death of macrophages contributes to atheroma formation. Oxidation renders low-density lipoprotein (LDL) cytotoxic to human monocyte-macrophages. Lipoprotein-associated phospholipase A2 (Lp-PLA2), also termed platelet-activating factor acetylhydrolase, hydrolyses oxidised phospholipids. Inhibition of Lp-PLA2 by diisopropyl fluorophosphate or Pefabloc (broad-spectrum serine esterase/protease inhibitors), or SB222657 (a specific inhibitor of Lp-PLA2) did not prevent LDL oxidation, but diminished the ensuing toxicity and apoptosis induction when the LDL was oxidised, and inhibited the rise in lysophosphatidylcholine levels that occurred in the inhibitors' absence. Hydrolysis products of oxidised phospholipids thus account for over a third of the cytotoxic and apoptosis-inducing effects of oxidised LDL on macrophages.
Phospholipid synthesis in Escherichia coli. Characteristics of fatty acid transfer from acyl-acyl carrier protein to sn-glycerol 3-phosphate. (1981)

Two kinetically distinguishable sn-glycerol 3-phosphate (glycerol-P) acryltransferase activities were detected in Escherichia coli inner membranes using acyl-acyl carrier protein (ACP) substrates. The first system was characterized as having a Michaelis constant (Km) for glycerol-P of 90 microM and utilized palmitoyl-ACP to form primarily 1-acylglycerol-P. Palmitoyl-CoA and cis-vaccenoyl-ACP were also utilized by this system but, with these substrates, significantly more phosphatidic acid was formed as compared to palmitoyl-ACP. Although palmitoyl-ACP and palmitoyl-CoA had kinetically indistinguishable glycerol-P sites, distinct acyl donor binding sites were inferred from kinetic experiments using acyl carrier protein as an acyltransferase inhibitor. A second enzyme system, characterized as having a Km for glycerol-P of 700 microM, was found using palmitoyl-ACP as a substrate. This acyltransferase had a slightly higher pH optimum than the low Km acyltransferase activity, and phosphatidic acid was the major product. Two degradative reactions were identified in this system. One reaction yielded diacylglycerol when palmitoyl-ACP was the substrate. The other degradative reaction produced glycerol. Glycerol was formed in all incubations but was most pronounced when palmitoyl-ACP was the substrate.
Tumor-Infiltrating Programmed Death Receptor-1+ Dendritic Cells Mediate Immune Suppression in Ovarian Cancer (2011)

Within the ovarian cancer microenvironment, there are several mechanisms that suppress the actions of antitumor immune effectors. Delineating the complex immune microenvironment is an important goal toward developing effective immune-based therapies. A dominant pathway of immune suppression in ovarian cancer involves tumor-associated and dendritic cell (DC)-associated B7-H1. The interaction of B7-H1 with PD-1 on tumor-infiltrating T cells is a widely cited theory of immune suppression involving B7-H1 in ovarian cancer. Recent studies suggest that the B7-H1 ligand, programmed death receptor-1 (PD-1), is also expressed on myeloid cells, complicating interpretations of how B7-H1 regulates DC function in the tumor. In this study, we found that ovarian cancer-infiltrating DCs progressively expressed increased levels of PD-1 over time in addition to B7-H1. These dual-positive PD-1(+) B7-H1(+) DCs have a classical DC phenotype (i.e., CD11c(+)CD11b(+)CD8(-)), but are immature, suppressive, and respond poorly to danger signals. Accumulation of PD-1(+)B7-H1(+) DCs in the tumor was associated with suppression of T cell activity and decreased infiltrating T cells in advancing tumors. T cell suppressor function of these DCs appeared to be mediated by T cell-associated PD-1. In contrast, ligation of PD-1 expressed on the tumor-associated DCs suppressed NF-κB activation, release of immune regulatory cytokines, and upregulation of costimulatory molecules. PD-1 blockade in mice bearing ovarian cancer substantially reduced tumor burden and increased effector Ag-specific T cell responses. Our results reveal a novel role of tumor infiltrating PD-1(+)B7-H1(+) DCs in mediating immune suppression in ovarian cancer.
Comparative neurovirulence of selected vesicular stomatitis virus temperature-sensitive mutants of complementation groups II and III (1981)

Weanling mice were inoculated intracerebrally with selected vesicular stomatitis virus (VSV) complementation group II and III temperature-sensitive (ts) mutants. Of the VSV ts mutants studied, only ts G32, a group III complementation mutant, appeared neurovirulent. Interestingly, neither the capacity to replicate in central nervous system tissue nor the ability to replicate in certain neurally derived continuous cell lines at semipermissive or nonpermissive temperatures appeared different among the VSV ts mutants employed. Finally, the pathological alterations in central nervous system tissue produced by VSV ts G32 were entirely different than those produced by G31 VSV ts in the group III mutant. These studies support the hypothesis that both the virological and neuropathological features produced by different VSV ts mutants are dependent upon the unique characteristics of each mutant, rather than upon a common biochemical defect shared by all members of a complementation group.
RETRACTED: KSHV vFLIP Is Essential for the Survival of Infected Lymphoma Cells (2004)

Primary effusion lymphomas (PELs) associated with infection by the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) have constitutive nuclear factor (NF)-kappaB activity that is essential for their survival, but the source of this activity is unknown. We report that viral FADD-like interleukin-1-beta-converting enzyme [FLICE/caspase 8]-inhibitory protein (FLIP) activates NF-kappaB more potently than cellular FLIP in B cells and that it is largely responsible for NF-kappaB activation in latently infected PEL cells. Elimination of vFLIP production in PEL cells by RNA interference results in significantly decreased NF-kappaB activity, down-regulation of essential NF-kappaB-regulated cellular prosurvival factors, induction of apoptosis, and enhanced sensitivity to external apoptotic stimuli. vFLIP is the first virally encoded gene shown to be essential for the survival of naturally infected tumor cells.
Mitochondrial Oxidative Phosphorylation Compensation May Preserve Vision in Patients with OPA1-Linked Autosomal Dominant Optic Atrophy (2011)

Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.
Role of Leptin in Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Expression (2000)

Peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1), a cold-induced protein expressed in brown adipose tissue (BAT), plays a role in adaptive thermogenesis by up-regulating uncoupling proteins (UCP). Here, we explore its relationship to the thermogenic actions of leptin, which also up-regulates UCPs. We find that PGC-1 messenger RNA (mRNA) is markedly reduced in BAT of obese leptin-deficient (ob/ob mice) and leptin-unresponsive (db/db mice and Zucker diabetic fatty fa/fa rats) rodents. Whereas, after cold exposure (6 C for 7 h), PGC-1 mRNA increases 2.6-fold in BAT of lean +/+ rats, it rises only 30% in fa/fa rats. Four days after induction of hyperleptinemia (>30 ng/ml) in Wistar rats, by adenovirus gene transfer, PGC-1 mRNA in BAT was 2.3-fold and UCP-1, 4-fold above controls. In isolated white adipocytes, PGC-1 mRNA increased 4.4-fold within 6 h of incubation with 20 ng/ml of leptin. We conclude that leptin action is required for normal basal and cold-stimulated PGC-1 expression in BAT in rodents and that hyperleptinemia rapidly up-regulates its expression, at least in part, by direct action.
Public Stem Cell Banks: Considerations of Justice in Stem Cell Research and Therapy (2003)

Ruth R. Faden, Liza Dawson, Alison S. Bateman-House, Dawn Mueller Agnew, Hilary Bok, Dan W. Brock, Aravinda Chakravarti, Xiao-Jiang Gao, Mark Greene, John A. Hansen, Patricia A. King, Stephen J. O'Brien, David H. Sachs, Kathryn E. Schill, Andrew Siegel, Davor Solter, Sonia M. Suter, Catherine M. Verfaillie, LeRoy B. Walters, John D. Gearhart, Public Stem Cell Banks: Considerations of Justice in Stem Cell Research and Therapy, The Hastings Center Report, Vol. 33, No. 6 (Nov. - Dec., 2003), pp. 13-27
Production of calves by transfer of nuclei from cultured inner cell mass cells. (1994)

We report here the isolation and in vitro culture of bovine inner cell mass (ICM) cells and the use of ICM cells in nuclear transfer to produce totipotent blastocysts that resulted in calves born. Of 15 cell lines represented in this study, 13 were derived from immunosurgically isolated ICM of 3 in vitro produced day 9-10 bovine blastocysts, while 2 lines were derived from single blastocysts. Approximately 70% of attempted cell lines became established cell lines when started from 3 ICMs. The ability to establish cell lines was dependent on the number of ICMs starting the line. Sire differences were noted in the ability of ICMs to establish cell lines and to form blastocysts. The cell lines were cultured as a low cell density suspension in the medium CR1aa plus selenium, insulin, and transferrin (SIT) and 5% fetal calf serum (FCS) for 6-101 days before use in nuclear transfer, at which time some had multiplied to more than 2000 cells. If allowed to aggregate, cells of established cell lines formed embryoid bodies. A total of 659 nuclear transfer clones were made by fusing the ES cells into enucleated oocytes with polyethylene glycol; 460 of these fused, based on cleavage (70%). After culture of the clones for 7 days in vitro in CR1aa/SIT/5% FCS, 109 (24%) of those fused became blastocysts. Thirty-four blastocysts were transferred into uteri of 27 cows, and 13 cows (49%) became pregnant. Four of the 13 cows gave birth to 4 normal calves. DNA typing showed the calves to be derived from the respective sires of the cell lines. The calves were derived from cultures of less than 28 days.
Industrial perspective on X-ray data collection and analysis (2005)

Protein crystallography methods applied by research teams in the pharmaceutical industry to support the process of discovery of new medicines are not greatly different from those used by academic structural biology groups. However, owing to the specific aims of the pharmaceutical industry, the approaches and working practices are often quite distinct. This applies to both the determination of novel structures of drug targets and complexes of these targets with potential drugs. To make any significant impact on ongoing medicinal chemistry projects, crystal structures have to be delivered on time and must provide answers to specific questions. Owing to the high number of crystal structures typically solved by industrial research groups, development of technology and computational methods which speed up the process and increase throughput is of vital importance. This paper presents an overview of current approaches to X-ray data collection and processing within the industrial environment, with examples of how technology is used to address the challenges structural biology faces in this "high-throughput-everything" period.
Elicitation of a systemic and protective anti-melanoma immune response by an IL-2-based vaccine. Assessment of critical cellular and molecular parameters. (1995)

We have established a model for the immunologic rejection of melanoma cells. Using a receptor-mediated, adenovirus-augmented gene delivery system (transferrinfection) we have shown that, upon transfection with an IL-2 gene construct, MHC class I+/class II- murine M-3 cells lose their tumorigenicity in both athymic and euthymic mice. More importantly, we found that these melanoma cells, which produce high levels of IL-2, can be used to induce a long-lasting anti-tumor immune response in syngeneic euthymic DBA/2 mice but not in athymic animals. This immune response, which can also be elicited by coadministration of nonmodified, irradiated M-3 cells and IL-2-transduced fibroblasts, results in the rejection of a subsequent challenge with M-3 cells or, in the elimination of preexisting M-3 cancer cell deposits. We found that transfer of T cell-enriched, but not of T cell-depleted, splenocytes from immunized mice conferred protection against M-3 cells, but not against unrelated KLN 205 cancer cells. Transfer of either CD4+ or CD8+ T cells led to only partial protection against challenge with wild-type M-3 cells. Our further observations that T cell-enriched, but not T cell-depleted splenocytes of immunized animals are capable of tumor-specific lytic activity and that this activity resides in the CD8+ cell population are compatible with the assumption that MHC class I-restricted T cell cytotoxicity is a biologically relevant effector mechanism in this model. That other mechanisms also contribute to melanoma cell destruction is evidenced by the presence of large numbers of macrophages and granulocytes in addition to T cells at the challenge sites of immunized mice.