gebhart/patrepeval huggingface dataset:
Conformational Stability Is a Determinant of Ribonuclease A Cytotoxicity (2000)

Onconasetrade mark, a homolog of bovine pancreatic ribonuclease A (RNase A) with high conformational stability, is cytotoxic and has efficacy as a cancer chemotherapeutic agent. Unlike wild-type RNase A, the G88R variant is toxic to cancer cells. Here, variants in which disulfide bonds were removed from or added to G88R RNase A were used to probe the relationship between conformational stability and cytotoxicity in a methodical manner. The conformational stability of the C40A/G88R/C95A and C65A/C72A/G88R variants is less than that of G88R RNase A. In contrast, a new disulfide bond that links the N and C termini (residues 4 and 118) increases the conformational stability of G88R RNase A and C65A/C72A/G88R RNase A. These changes have little effect on the ribonucleolytic activity of the enzyme or on its ability to evade the cytosolic ribonuclease inhibitor protein. The changes do, however, have a substantial effect on toxicity toward human erythroleukemia cells. Specifically, conformational stability correlates directly with cytotoxicity as well as with resistance to proteolysis. These data indicate that conformational stability is a key determinant of RNase A cytotoxicity and suggest that cytotoxicity relies on avoiding proteolysis. This finding suggests a means to produce new cancer chemotherapeutic agents based on mammalian ribonucleases.
Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu (2007)

Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination.
Serum Levels of Galectin-3: Possible Association with Fibrosis, Aberrant Angiogenesis, and Immune Activation in Patients with Systemic Sclerosis (2012)

Galectin-3 may be related to the developmental process of skin sclerosis in dcSSc and of DU and pulmonary vascular involvements in total SSc.
Characteristics and epitope mapping of a cloned human autoantigen La. (1988)

The La (SS-B) polypeptide is a ribonucleoprotein against which high titer antinuclear antibodies (ANA) react in the human autoimmune disease primary Sjögren's syndrome. To identify the autoepitopes with which the ANA anti-La (anti-SS-B) reacts, we isolated a 1.4-kb cDNA clone for La from a lambda gt10 library made from a human Burkitt's cell line. This clone contained an open reading frame of 1065 bp, encoding a 40.1-kDa polypeptide that corresponded to the carboxyl-terminal end of the La protein. The predicted polypeptide sequence of the recombinant protein was highly charged and unrelated to any previously published sequence. We also compared this clone to a previously published cDNA sequence for La and demonstrated significant differences, particularly that the open reading frame in our cDNA continued for 926 additional bases 3' to a putative termination codon in the previously reported sequence. The recombinant La protein was expressed in Escherichia coli and tested for reactivity with 200 sera containing ANA of various specificities. Only the sera containing anti-La antibodies reacted with the cloned La. By expressing subclones of the La cDNA as fusion proteins with beta-galactosidase, we have localized at least one epitope for the binding of anti-La antibodies to the carboxyl-terminal 103 amino acids of the La protein. No anti-La binding could be demonstrated to the region of the La protein that had previously been predicted to contain an autoepitope for the binding of anti-La (SS-B) antibodies. Studies of cloned autoepitopes could provide important clues to the role ANA play in disease and lead to targeted intervention in the treatment of primary Sjögren's syndrome.
The molecular basis of class II MHC allelic control of T cell responses (1991)

To identify the molecular basis for the effects of MHC molecule polymorphism on T cell responses, we have combined functional T cell response testing with measurements of peptide binding to the class II MHC molecules on transfected cells. Our studies identify a small subset of spatially localized polymorphic residues of the E alpha E beta dimer (strand residue beta 29, and helix residues beta 72 and beta 75) regulating cytochrome c peptide presentation by two distinct mechanisms. The first effect is on quantitative control of net peptide binding. The replacement of the valine found at position beta 29 in E beta k with the glutamic acid found in E beta b results in a selective loss of pigeon cytochrome peptide but not moth cytochrome peptide binding to the resultant mutant E alpha E beta k molecule. Reciprocally, the replacement of glutamic acid at beta 29 in E beta b with valine results in a gain of pigeon peptide binding. These changes in binding parallel changes in T cell responses in vitro to these peptide-E alpha E beta combinations and mirror the in vivo immune response gene phenotypes of mice expressing E alpha E beta k and E alpha E beta b. E alpha E beta s molecules, which have a beta 29 glutamic acid, are nevertheless able to bind and present pigeon cytochrome peptides, and this is due to changes in helix residues beta 72 and beta 75 that compensate for the negative effect of the beta 29 glutamic acid. The second activity is a critical change in the conformation of the peptide bound to the same extent by distinct MHC molecules, as revealed by changes in T cell responses to moth cytochrome peptides presented by two E alpha E beta molecules differing only at position beta 29. Both of these effects can be ascribed to a single polymorphic residue modeled to be inaccessible to TCR contact (beta 29), providing a striking demonstration of how MHC molecule polymorphism can modify T cell-dependent immune responses without direct physical participation in the receptor recognition event.
The absorption and fluorescence spectra of rare earth ions in silica-based monomode fiber (1988)

Rare-earth ions have been systematically incorporated into the cores of silica-based optical fibers, and the absorption and fluorescence spectra have been measured. The results provide basic data for a wide range of possible future fiber-based devices. For specific telecommunications applications, ions that could be useful for sources in the 1.3- mu m and 1.5- mu m low-loss windows are identified. It is suggested that Er/sup 3+/, Nd/sup 3+/, and Tm/sup 3+/ are the most promising ions for semiconductor pumping with GaAs-based laser diodes.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Functional Expression of Human Golgi CMP-Sialic Acid Transporter in the Golgi Complex of a Transporter-Deficient Chinese Hamster Ovary Cell Mutant (1998)

We recently described the cloning of putative human CMP-sialic acid transporter (hCST) cDNA [Ishida, N. et al. (1996) J. Biochem. 120, 1074-1078]. The hCST cDNA coded for a hydrophobic protein with an amino acid sequence showing a high degree of similarity (92% identity) to that of murine CMP-sialic acid transporter. In this report, we demonstrate that hCST corrects the CMP-sialic acid transporter-deficient phenotype of CHO-derived Lec2 cells, as judged from the recovery of WGA-sensitivity by transformants, and the recovery of CMP-sialic acid transporting ability by microsomal vesicles prepared from them. A peptide antibody against the C-terminus of the hCST protein detected the cDNA products expressed in the microsomes of the transformants. The subcellular localization of the hCST protein in the Golgi membrane was demonstrated by immunofluorescence microscopy, using the hCST-specific antibody. These results clearly indicate that hCST cDNA encodes the human CMP-sialic acid transporter protein. Plasma membrane-selective permeabilization combined with immunofluorescence microscopy provided strong evidence that the C-terminus of the human CMP-Sia transporter is exposed to the cytosol on the outer surface of the Golgi membrane.
Delayed DNA damage associated with mitotic catastrophe following X-irradiation of HeLa S3 cells* (1998)

Partial loss of the radiation G2/M checkpoint is thought to be an early event in cell immortalization. One of the attributes of immortalized cell lines is an increase in susceptibility to induction of genomic instability by clastogenic agents. Recently we have shown that in irradiated HeLa cells cell cycle delays in late S and G2 lead to overaccumulation of cyclin B1 and that enhanced intracellular levels of this positive regulator of the cell cycle is correlated with cyclin-dependent kinase activation, spontaneous premature chromosome condensation and subsequent mitotic catastrophe occurring following irradiation. Previous studies have shown that spontaneous premature chromosome condensation and mitotic catastrophe are independent of apoptosis. This report shows that 40 h following X-irradiation of HeLa S3 cells, and subsequent to mitotic catastrophe, DNA strand breaks appear which are chemically distinct from those initially produced by ionizing radiation. This delayed damage is recognized by terminal transferase and thus involves generation of free 3'-OH ends. Pulse field gel electrophoresis analysis of DNA size distributions shows that DNA fragments of approximately 40 kbp and smaller are produced. As strand breaks produced as a direct result of irradiation are generally repaired within a few hours after exposure to X-rays at the doses used, these results describe a novel mechanism for generation of DNA damage occurring a day or more following irradiation. These results may be pertinent to the understanding of mechanisms underlying the delayed lethal effects of irradiation and may provide an initiating mechanism for radiation-induced genomic instability.
Drosophila As a Genetically Tractable Model for Social Insect Behavior (2016)

The relatively simple communication, breeding, and egg-making systems that govern reproduction in female Drosophila retain homology to eusocial species in which these same systems are modified to the social condition. Despite having no parental care, division of labor, or subfertile caste, Drosophila may nonetheless offer a living test of certain sociobiological hypotheses framed around gene function. In this review, we make this case, and do so around the recent discovery that the non-social fly, Drosophila melanogaster, can respond to the ovary-suppressing queen pheromone of the honey bee Apis mellifera. Here, we first explain the sociobiological imperative to reconcile kin theory with molecular biology, and qualify a potential role for Drosophila. Then, we offer three applications for the fly-pheromone assay. First, the availability and accessibility of massive mutant libraries makes immediately feasible any number of open or targeted gene screens against the ovary-inhibiting response. The sheer tractability of Drosophila may therefore help to accelerate the search for genes in pheromone-responsive pathways that regulate female reproduction, including potentially any that are preserved with modification to regulate worker sterility in response to queen pheromones in eusocial taxa. Secondly, Drosophila's powerful Gal4/UAS expression system can complement the pheromone assay by driving target gene expression into living tissue, which could be well-applied to the functional testing of genes presumed to drive ovary activation or de-activation in the honey bee or other eusocial taxa. Finally, coupling Gal4 with UAS-RNAi lines can facilitate loss-of-function experiments against perception and response to the ovary inhibiting pheromone, and do so for large numbers of candidates in systematic fashion. Drosophila's utility as an adjunct to the field of insect sociobiology is not ideal, but retains surprising potential.
The role of dopamine in epilepsy (1996)

The clinical benefits of dopamine agonists in the management of epilepsy can be traced back over a century, whilst the introduction of neuroleptics into psychiatry practice 40 years ago witnessed the emergence of fits as a side effect of dopamine receptor blockade. Epidemiologists noticed a reciprocal relationship between the supposed dopaminergic overactivity syndrome of schizophrenia and epilepsy, which came to be regarded as a dopamine underactivity condition. Early pharmacological studies of epilepsy employed nonselective drugs, that often did not permit dopamine's antiepileptic action to be clearly dissociated from that of other monoamines. Likewise, the biochemical search for genetic abnormalities in brain dopamine function, as predeterminants of spontaneous epilepsy, proved largely inconclusive. The discovery of multiple dopamine receptor families (D1 and D2), mediating opposing influences on neuronal excitability, heralded a new era of dopamine-epilepsy research. The traditional anticonvulsant action of dopamine was attributed to D2 receptor stimulation in the forebrain, while the advent of selective D1 agonists with proconvulsant properties revealed for the first time that dopamine could also lower the seizure threshold from the midbrain. Whilst there is no immediate prospect of developing D2 agonists or D1 antagonists as clinically useful antiepileptics, there is a growing awareness that seizures might be precipitated as a consequence of treating other neurological disorders with D2 antagonists (schizophrenia) or D1 agonists (parkinsonism).
Development and Application of the Maglev Transportation System (2008)

The development of the Maglev train is a very important achievement in passenger transportation for the 20th century. Based on the recent information this paper describes the development of different Maglev systems, the application of Maglev for passenger transportation, and the experience of promoting the Maglev transportation in China.
TNF-Mediated Activation of the Stress-Activated Protein Kinase Pathway: TNF Receptor-Associated Factor 2 Recruits and Activates Germinal Center Kinase Related (1999)

TNF-induced activation of stress activated protein kinases (SAPKs, Jun NH2-terminal kinases) requires TNF receptor associated factor 2 (TRAF2). TRAF2 is a potent activator of a 95-kDa serine/threonine kinase termed germinal center kinase related (GCKR, also referred to as KHS1), which signals activation of the SAPK pathway. Consistent with a role for GCKR in TNF- induced SAPK activation, a kinase-inactive mutant of GCKR is a dominant negative inhibitor of TRAF2-induced SAPK activation. Here we show that TRAF2 interacts with GCKR. This interaction depended upon the TRAF domain of TRAF2 and the C-terminal 150 aa of GCKR. The full activation of GCKR by TRAF2 required the TRAF2 RING finger domain. TNF treatment of a T cell line, Jurkat, increased both GCRK and SAPK activity and enhanced the coimmunoprecipitation of GCKR with TRAF2. Similar results were found with the B cell line HS-Sultan. These findings are consistent with a model whereby TNF signaling results in the recruitment and activation of GCKR by TRAF2, which leads to SAPK activation.
Rat melanin-concentrating hormone messenger ribonucleic acid expression: marked changes during development and after stress and glucocorticoid stimuli (1992)

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide first isolated from fish and rats. MCH may be involved in the control of the hypothalamic-pituitary-adrenocortical axis and, more generally, of specific goal-oriented behaviors and homeostatic functions in mammals. In this paper we examine 1) the cellular distribution of MCH gene transcripts in the rat central nervous system, 2) the changes in neuronal expression of MCH mRNA during rat development, and 3) the effects of stress and hormonal stimuli on rat MCH (rMCH) gene activity. Northern blot analysis and in situ hybridization histochemistry show that mature rMCH mRNA (1.0 kilobase) is very abundant in the zona incerta and the dorsolateral hypothalamus. While this is in agreement with previous peptide mapping by immunohistochemical techniques, a surprising new result is that a few clusters of rMCH mRNA-containing cells are found outside the hypothalamus, in the olfactory tubercle and the pontine tegmentum. Developmentally, rMCH mRNA is detected on embryonic day 18; its level increases gradually during early postnatal life and rises abruptly at weaning to reach a constant value in adult rats. In addition, striking variations in rMCH mRNA length occur during postnatal development and are found to be variations in the polyadenylate tail. Interestingly, this structural modification appears to be independent of the increase in rMCH mRNA levels. The regulation of rMCH mRNA expression by glucocorticoids and chronic stress is examined by Northern blot analysis. Chronic intermittent footshock stress causes a 58% or 29% decrease in rMCH mRNA content in the whole hypothalamus after a 1- or 3-day regimen, respectively. In contrast, the rMCH mRNA level returns to normal after a 7-day regimen. Two weeks after adrenalectomy (ADX) the whole hypothalamus rMCH mRNA content decreases 2.5-fold, but rises close to the control value 3 weeks after ADX. Dexamethasone administration 2 weeks after ADX not only reverses the fall in rMCH mRNA, it even provokes a slight increase (123% of control). No change in rMCH mRNA length is observed after chronic stress or ADX and dexamethasone injection. These results provide evidence for a negative regulation of rMCH gene expression by stress and suggest a major role for glucocorticoids in a positive feedback control of rMCH gene activity.
Installation of Concentric Subsea Completions from a Jack-Up in the Welland Field: A Case History (1991)

ABSTRACT During the Spring/Summer of 1990, Arco British Limited., on behalf of the Welland Partnership, carried out the installation of three subsea completions from a jack-up in the Welland Field which is located in the UK sector of the Southern North Sea. The subsea completion was of the concentric type and utilised a first of its kind metal to metal sealing annulus valve in the tubing hanger for annulus access/isolation. The completions were landed in wellheads that had been installed during the previous summer as part of the conversion process from three manufacturer's mudline suspension systems (MLS) to a single type subsea wellhead incorporating a common profile. This paper will present a summary of the pre-planning and experience gained during the installation activities of both the wellhead conversion equipment and the completion equipment. Insight into the problems that arose will be covered as well as highlights of the successes achieved. Recommendations for future completions of this type will be presented.
Controlling Culture Dynamics for the Expansion of Hematopoietic Stem Cells (2001)

The ex vivo expansion of hematopoietic stem cells (HSCs) is the subject of intense commercial and academic interest due to the potential of HSCs to be a renewable source of material for cellular therapeutics. Unfortunately, because methodologies have not yet been developed to grow clinically relevant numbers of HSCs (or their derivatives) consistently, the potential of this technology is limited. Manipulation of the in vitro culture microenvironment, primarily through cytokine supplementation, has been the predominant approach in studies attempting to expand primary human HSC numbers in vitro. While promising results have been obtained, it is becoming clear that novel methods must be developed before cellular therapies using these stem cells can become routine. Ideally, bioprocesses must be designed to target specifically the growth of stem cell populations while incorporating positive and negative feedback from potentially dynamic mature and maturing cell populations. The product of these culture systems should consist of not only HSCs, but also of cells that allow the engraftment of HSCs and, ideally, cells responsible for the immediate or accelerated functional support of patients. Development of such "designer transplants" will require combining optimal culture conditions capable of amplifying HSC numbers with novel approaches for finely controlling the number, functional capabilities, and characteristics of potentially therapeutic cells in these very complex cell culture systems.
Cancer Vaccines: The Role of Tumor Burden in Tipping the Scale Toward Vaccine Efficacy (2005)

Cancer vaccines have significant theoretical therapeutic advantages over more standard methods of cancer treatment. If a robust cellular immune response could be elicited, then immunologic memory could be long lasting, eradicatingcancerattimesquitedistantfrominitialtherapy.Tcells potentiallycanmigratetotumorsites,leavethevasculature, and invade tissues eradicating deep-seated disease at any metastatic site. Furthermore, T cells are extremely specific in their attack, as opposed to the generalized toxicities seen with some chemotherapies. Finally, as long as there is antigen available for T-cell recognition, T cells have the potential to continue to respond until disease is eradicated. In this issue of the Journal of Clinical Oncology, investigators fromWalterReedArmyMedicalCenter(Washington,DC) and the M.D. Anderson Cancer Center (Houston, TX) present data from a trial in which breast cancer patients were immunized with a vaccine targeting the HER-2/neu oncogenic protein to prevent disease relapse. 1
Magnetic Resonance Characterization of Blood Coagulation In Vitro (1991)

To optimize magnetic resonance (MR) methods of characterizing thrombi, further studies of biologic determinants of spinlattice (T1) and spin-spin (T2) relaxation times of thrombi are needed. As a step toward evaluating the influence of thrombus cellular composition on MR properties, the authors evaluated the effect of platelet depletion on MR relaxation times of in vitro blood clots. Blood from 13 fasting normal men was collected into sodium citrate (3.8%) and centrifuged ( [10,000 X g] X 5-10 minutes). Platelet-poor specimens (less than 20,000 per mm3) were reconstituted from the plasma and packed erythrocytes to match precentrifugation hematocrit levels. T1 and T2 measurements were made at 20 MHz within three to six hours of initiating clotting. The mean T1 value for platelet-rich (normal) specimens was 1117 +/- 86 mseconds versus 1119 +/- 68 mseconds for the platelet-poor specimens (P greater than .90). The mean T2 value for platelet-rich (normal) specimens was 616 +/- 130 mseconds versus 434 +/- 79 mseconds for the platelet-poor specimens (P less than .001). The mean water content in the platelet-rich (normal) specimens was 79.5% +/- 1.2% versus 80.0% +/- 1.2% in the platelet-poor specimens (P greater than .50). In summary, platelet depletion by buffy coat removal significantly shortens MR T2 values of in vitro clot. These data suggest that thrombus cellular composition, other than erythrocytes, alters MR relaxation times of clotted blood.