gebhart/patrepeval huggingface dataset:
Morphological Differences between Circulating Tumor Cells from Prostate Cancer Patients and Cultured Prostate Cancer Cells (2014)

Circulating tumor cell (CTC) enumeration promises to be an important predictor of clinical outcome for a range of cancers. Established CTC enumeration methods primarily rely on affinity capture of cell surface antigens, and have been criticized for underestimation of CTC numbers due to antigenic bias. Emerging CTC capture strategies typically distinguish these cells based on their assumed biomechanical characteristics, which are often validated using cultured cancer cells. In this study, we developed a software tool to investigate the morphological properties of CTCs from patients with castrate resistant prostate cancer and cultured prostate cancer cells in order to establish whether the latter is an appropriate model for the former. We isolated both CTCs and cultured cancer cells from whole blood using the CellSearch® system and examined various cytomorphological characteristics. In contrast with cultured cancer cells, CTCs enriched by CellSearch® system were found to have significantly smaller size, larger nuclear-cytoplasmic ratio, and more elongated shape. These CTCs were also found to exhibit significantly more variability than cultured cancer cells in nuclear-cytoplasmic ratio and shape profile.
Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis. (1994)

In vitro T-cell receptor-induced programmed cell death in both activated T cells from human immunodeficiency virus-seronegative (HIV-) donors and resting T cells from HIV+ donors was substantially influenced by cytokines. Addition of exogenous recombinant "type 1" lymphokines interferon gamma and interleukin 2 (IL-2), as well as the macrophage-produced IL-12, which favor cell-mediated T-cell responses, blocks both systems of T-lymphocyte programmed cell death. In contrast, the "type 2" lymphokines IL-4 and IL-10, which favor antibody responses, either had no effect or enhanced these systems of in vitro T-cell programmed cell death. A role for endogenously produced cytokines was suggested by the inhibition of T-cell receptor-mediated death by antibodies against IL-4 and IL-10 and its enhancement by anti-IL-12 in cultures containing monocytes. These results demonstrate that the functional properties of type 1 and type 2 cytokine classes may be further extended to include their effects on T-cell programmed cell death and their possible role in the pathogenesis of HIV infection.
Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway (2012)

Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C-terminal domain, which is typical of other SAM-dependent O-methyltransferases, and an N-terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3-dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans.
A soluble form of a receptor for subgroup A avian leukosis and sarcoma viruses (ALSV-A) blocks infection and binds directly to ALSV-A (1994)

A receptor that confers susceptibility to infection by subgroup A avian leukosis and sarcoma viruses (ALSV-A) has been described (P. Bates, J. A. T. Young, and H. E. Varmus, Cell 74:1043-1051, 1993). A soluble form of the receptor was generated to determine whether this protein interacts directly with virus particles in the absence of other cell surface factors. The soluble protein comprised the extracellular region of the ALSV-A receptor fused to an antibody epitope tag and six histidine residues. Preincubating this protein with virus led to an efficient block to infection of avian cells by ALSV-A but had no effect on infection by ALSV-B, ALSV-C, or ALSV-D. Furthermore, an antibody directed against the introduced epitope tag immunoprecipitated ALSV-A particles bound to the soluble receptor. In contrast, other ALSV subgroups were not immunoprecipitated by this procedure. These data demonstrate that the cloned receptor interacts directly with ALSV-A and discriminates between different ALSV subgroups at the level of virus binding.
Substrate specificity of Escherichia coli thymidine phosphorylase (2007)

Substrate specificity of Escherichia coli thymidine phosphorylase to thymidine derivatives modified at 5' -, 3' -, and 2' ,3' - positions of the sugar moiety was studied. Equilibrium and kinetic constants (K(m), K(I), k(cat)) of the phosphorolysis reaction have been determined for 20 thymidine analogs. The results are compared with X-ray and molecular dynamics data. The most important hydrogen bonds in the enzyme-substrate complex are revealed.
Hemostatic factors in rabbit limb lymph: relationship to mechanisms regulating extravascular coagulation (1998)

Mechanisms regulating extravascular coagulation in interstitial fluids of peripheral tissues are poorly understood, since measurements of hemostatic factors in these fluids are unavailable. Because lymph from a body region reflects the composition of its interstitial fluid, we measured hemostatic factors in limb lymph of rabbits both as activity and as antigen. Mean lymph-to-plasma activity ratios were the following: fibrinogen, 0.28; prothrombin, 0.26; factor X, 0.27; factor VII, 0.17; and factors V and VIII, 0.08. All lymph fibrinogen was clottable; fibrin degradation products were absent. Lymph von Willebrand factor antigen was < 10% of plasma antigen and consisted primarily of lower molecular weight multimers. Mean lymph-to-plasma activity ratio for antithrombin was 0.38 and for tissue factor pathway inhibitor the ratio was 0.40. Low levels of antithrombin-factor Xa were measurable in lymph. The data are compatible with a basal factor VIIa-tissue factor-catalyzed extravascular activation of factor X that is prevented from progressing to generation of fibrin in limb interstitial fluid and lymph by low levels of factor VIII and factor V and by the inhibitory activity of antithrombin and tissue factor pathway inhibitor.
The Role of T Cell Antagonism and Original Antigenic Sin in Genetic Immunization (2002)

To counter highly mutable pathogens like HIV-1, a number of vaccines are being developed to deliver multiple mutant forms of viral Ags to provoke multivalent antiviral CTLs. However, it is uncertain whether such multiple mutant epitope vaccines will generate the diverse CTL responses desired or will instead create immune interference. To characterize the role of immune interference by mutant epitopes in this process, we have tested a "worst case" scenario in which the immunodominant epitope of OVA (SIINFEKL) and its in vitro TCR antagonist (SIINFEDL) have been used to genetically immunize C57BL/6 mice. We demonstrate here that sequential delivery of these mutant epitopes provokes original antigenic sin in CD8 T cells as demonstrated by attenuation of CTLs, intracellular IFN-gamma production, and MHC I peptide-tetramer staining. By contrast, simultaneous exposure of the immune system to this agonist/antagonist pair not only fails to generate T cell antagonism in vivo, but also avoids original antigenic sin. These observations suggest that simultaneous immunization with vaccines containing mutant epitopes, even T cell antagonists, can indeed generate a diverse array of T cell responses and that at least some immune interference can be avoided by delivering mutant Ags to the immune system simultaneously.
The daily excretion of bacteria in the feces of healthy men (1909)

During the past year we have examined at intervals of about two weeks the fecal bacteria of each individual in a group of twelve men who were the subjects of a prolonged metabolism experiment. These men were fed a mixed diet, in quantity according to their choice at the beginning of the experiment. Altogether we have examined bacteriologically 266 stools. The quantity of bacteria in each of these stools was estimated by two different methods of microscopic counting and in about half of them the quantity of bacterial dry substance was also estimated by the gravimetric method of Strasburger.
Regulation of the immune response to peptide antigens: differential induction of immediate-type hypersensitivity and T cell proliferation due to changes in either peptide structure or major histocompatibility complex haplotype. (1991)

The immunodominant CD4 T cell epitope of the bacteriophage lambda cI repressor protein in several inbred mouse strains can be represented by a peptide encompassing amino acids 12-26. Here, we show that this peptide, and a variety of its sequence variants, can induce immediate-type hypersensitivity in mice. 12-26 variants that differ by as little as single amino acid residues deviate greatly in their ability to induce hypersensitivity. Further, differences in major histocompatibility complex class II alleles appear to be as influential as changes in peptide structure in determining whether hypersensitivity is developed. The ability of a given peptide-class II combination to induce hypersensitivity correlates with production of peptide-specific antibody, but not with ability or inability to induce a T cell proliferative response. Administration of anti-interleukin 4 (IL-4) mAb prevents the development of hypersensitivity, and analysis of cytokine production by T cell hybridomas derived from peptide-immunized mice suggests that whether a given peptide-class II combination can induce hypersensitivity depends on its ability to induce IL-4 production. The data demonstrate that changes in the nature of the epitope(s) recognized by the CD4 T cell population can result in qualitative differences in the response elicited in this population, ultimately leading to dramatic quantitative and qualitative variations in the effector phase of the immune response.
Impaired metabolic modulation of α-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle (1998)

The neuronal isoform of nitric oxide synthase (nNOS) is highly expressed in mammalian skeletal muscle, but its functional role has not been defined. NO has been implicated in the local metabolic regulation of blood flow in contracting skeletal muscle in part by antagonizing sympathetic vasoconstriction. We therefore hypothesized that nNOS in skeletal muscle is the source of the NO mediating the inhibition of sympathetic vasoconstriction in contracting muscle. In the mdx mouse, a model of Duchenne muscular dystrophy in which dystrophin deficiency results in greatly reduced expression of nNOS in skeletal muscle, we found that the normal ability of skeletal muscle contraction to attenuate alpha-adrenergic vasoconstriction is defective. Similar results were obtained in mutant mice that lack the gene encoding nNOS. Together these data suggest a specific role for nNOS in the local metabolic inhibition of alpha-adrenergic vasoconstriction in active skeletal muscle.
Agonist Activity of Bimatoprost, Travoprost, Latanoprost, Unoprostone Isopropyl Ester and Other Prostaglandin Analogs at the Cloned Human Ciliary Body FP Prostaglandin Receptor (2002)

We have determined the agonist activity of a number of natural prostaglandins and prostaglandin analogs at the FP prostaglandin receptor cloned from a human ciliary body cDNA library using phosphoinositide (PI) turnover assays. Travoprost acid (EC50 = 3.2 +/- 0.6 nM) was the most potent agonist in these cells followed by bimatoprost free acid (17-phenyl-trinor PGF2alpha; EC50 = 5.8 +/- 2.6 nM), fluprostenol (EC50 = 6.1 +/- 1.5 nM), and latanoprost free acid (PHXA85; EC50 = 54.6 +/- 12.4 nM) which was 17-fold weaker (p < 0.001) than travoprost acid. Unoprostone and S-1033 were significantly (p < 0.001) weaker than travoprost acid. The amide prodrug, bimatoprost (EC50 = 694 +/- 293 nM), activated this FP receptor with an intermediate potency. The isopropyl ester prodrugs, travoprost (EC50 = 42.3 +/- 6.7 nM), latanoprost (EC50 = 126 +/- 347 nM) and unoprostone isopropyl ester (EC50 = 9,100 +/- 2,870 nM), also exhibited FP agonist activity. However, other compounds such as PGI2, bradykinin, histamine, and serotonin were inactive. The agonist activities of bimatoprost, unoprostone (UF-021), fluprostenol and acids of travoprost and latanoprost were antagonized by AL-8810 (11beta-fluoro- 15-epi-15-indanyl-PGF2alpha), an FP-receptor-selective antagonist (Ki = 1.0 - 2.1 microM; n = 3). These studies have demonstrated, for the first time, agonist activities of the currently known and marketed ocular hypotensive prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor.
Granulocyte Colony-Stimulating Factor for the Induction of T-Cell Tolerance (2007)

In recent years, investigators have unraveled a previously unrecognized role for granulocyte colony-stimulating factor (G-CSF) in the regulation of T-cell and dendritic cell functions. The experimental evidence in favor of G-CSF-mediated immune regulation includes the ability to skew T-cell cytokine secretion to T-helper type 2 responses, and to promote regulatory T-cell and tolerogenic dendritic cell differentiation. Accordingly, beneficial effects of G-CSF have been detected in animal models of immune-mediated diseases, including posttransplantation graft-versus-host disease, experimental autoimmune encephalomyelitis, lupus nephritis, inflammatory bowel disease, and diabetes. The growing body of evidence supporting a novel role for G-CSF in the induction of T-cell tolerance is reviewed herein.
ShockAbsorber: a TCP connection router (2002)

ShockAbsorber is a software router of TCP connections that supports load sharing across multiple TCP servers that share a set of virtual IP addresses. It consists of the executor, an O/S kernel extension that supports fast IP packet forwarding, and a user level manager process that controls it. The manager implements a novel dynamic load-sharing algorithm for allocation of TCP connections among servers according to their real-time load and responsiveness. This algorithm produces weights that are used by the executor to quickly select a server for each new connection request. The executor forwards client TCP packets to the servers without performing any TCP/IP header translations. Outgoing server-to-client packets are not handled by ShockAbsorber and can follow a separate network route to the clients. Depending on the workload traffic, the performance benefit of this half-connection method can be significant. Prototypes of ShockAbsorber were used to scale up several large and high-load Internet sites serving millions of TCP connections per hour.
Sequence analysis and expression of a cDNA clone encoding a 98‐kDa allergen in Dermatophagoides farinae (1999)

The study indicated that 98-kDa mite paramyosin is an important allergen.
Complete Translation of the Hepatitis C Virus Genome In Vitro: Membranes Play a Critical Role in the Maturation of All Virus Proteins except for NS3 (2005)

We developed an in vitro translation extract from Krebs-2 cells that translates the entire open reading frame of the hepatitis C virus (HCV) strain H77 and properly processes the viral protein precursors when supplemented with canine microsomal membranes (CMMs). Translation of the C-terminal portion of the viral polyprotein in this system is documented by the synthesis of NS5B. Evidence for posttranslational modification of the viral proteins, the N-terminal glycosylation of E1 and the E2 precursor (E2-p7), and phosphorylation of NS5A is presented. With the exception of NS3, efficient generation of all virus-specific proteins is CMM dependent. A time course of the appearance of HCV products indicates that the viral polyprotein is cleaved cotranslationally. A competitive inhibitor of the NS3 protease inhibited accumulation of NS3, NS4B, NS5A, and NS5B, but not that of NS2 or structural proteins. CMMs also stabilized HCV mRNA during translation. Finally, the formyl-[35S]methionyl moiety of the initiator tRNA(Met) was incorporated exclusively into the core protein portion of the polyprotein, demonstrating that translation initiation in this system occurs with high fidelity.
Development of supersaturatable self-emulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs (2005)

The supersaturatable self-emulsifying drug delivery system (S-SEDDS) represents a new thermodynamically stable formulation approach wherein it is designed to contain a reduced amount of a surfactant and a water-soluble cellulosic polymer (or other polymers) to prevent precipitation of the drug by generating and maintaining a supersaturated state in vivo. The S-SEDDS formulations can result in enhanced oral absorption as compared with the related self-emulsifying drug delivery systems (SEDDS) formulation and the reduced surfactant levels may minimise gastrointestinal surfactant side effects.
An engineered change in substrate specificity of ribulosebisphosphate carboxylase/oxygenase. (1990)

The potential for altering the specificity of ribulosebisphosphate carboxylase/oxygenase toward gaseous substrates is explored through a modest perturbation of the active site microenvironment. Specifically, replacement of active site Glu-48 with carboxy-methylcysteine is achieved in a two-step process in which the catalytically incompetent Cys-48 mutant protein is first generated and then treated with iodoacetic acid. This regimen of concerted site-directed mutagenesis and chemical modification, effectively lengthening the glutamyl side chain by insertion of a sulfur atom between the beta- and gamma-methylene groups, results in a protein possessing 4-6% of wild-type carboxylase activity. Concomitantly, the engineered enzyme exhibits a specificity factor 5-fold lower than that of wild-type enzyme. This represents the first example of a major change in substrate specificity, albeit in favor of oxygenation, effected by structural alteration of an active site side chain.
Modulation of novel DNA adducts during human uterine cervix cancer progression (2006)

Progressive accumulation of DNA lesions leads to genetic mutations that are central to the process of tumorigenesis. Human cervix provides an ideal system to determine progressive accumulation of DNA adducts in the target tissue because of its accessibility during routine diagnostic checkups. Uterine cervix samples from various pathologies, i.e. normal (n=13), inflammation (n=9), dysplasia (n=5) and different stages of invasive cancer (n=47), were analyzed for DNA adduct burden by modified 32P-postlabeling/TLC systems. Six subgroups of adducts were detected in the following descending order of polarities: P-1, P-2, PL-1, PL-2, L-1 and L-2 (P, polar; L, lipophilic; PL, between polar and lipophilic). No qualitative differences were observed in adduct profiles in the various cervix pathologies analyzed. However, significant quantitative differences were found. Previously known lipophilic adducts increased significantly from normal to cancer (144+/-61 to 503+/-51 adducts/10(9) nucleotides). Interestingly, the newly discovered polar adducts were present at 61- to 527-fold higher levels than lipophilic adducts. Of all the polar adducts, the known mutagenic lesion, 8-oxodeoxyguanosine, predominated in all cervix conditions. Notably, this lesion was elevated 27-fold in inflammation compared with normal cervix (51,058+/-9,863 versus 1,886+/-507 adducts/10(9) nucleotides). The P-1, PL-1, PL-2 and L-1 adducts were elevated 3- to 13-fold in inflammation compared with normal cervix, and were also higher in dysplasia and cancer. Our data suggest that inflammation may be involved in directing the course of disease progression by accumulating higher levels of DNA lesions. The data further suggest the biomarker potential of the newly detected array of DNA adducts.
A Role of the Fast ATP-gated P2X1 Cation Channel in Thrombosis of Small Arteries In Vivo (2003)

The P2X1 receptor is a fast ATP-gated cation channel expressed in blood platelets, where its role has been difficult to assess due to its rapid desensitization and the lack of pharmacological tools. In this paper, we have used P2X1-/- and wild-type mouse platelets, treated with apyrase to prevent desensitization, to demonstrate the function of P2X1 in the response to thrombogenic stimuli. In vitro, the collagen-induced aggregation and secretion of P2X1-deficient platelets was decreased, as was adhesion and thrombus growth on a collagen-coated surface, particularly when the wall shear rate was elevated. In vivo, the functional role of P2X1 could be demonstrated using two models of platelet-dependent thrombotic occlusion of small arteries, in which blood flow is characterized by a high shear rate. The mortality of P2X1-/- mice in a model of systemic thromboembolism was reduced and the size of mural thrombi formed after a laser-induced vessel wall injury was decreased as compared with normal mice, whereas the time for complete thrombus removal was shortened. Overall, the P2X1 receptor appears to contribute to the formation of platelet thrombi, particularly in arteries in which shear forces are high.
Calcium and the Prevention of Colon Cancer (1991)

Diet is a major determinant of colon cancer risk. Calcium may protect against colon cancer, presumably by binding cytotoxic bile acids and fatty acids. Numerous studies support this proposition. In subjects at risk for colon cancer oral calcium supplementation has been shown to reduce rectal epithelial proliferation rate, thereby supposedly decreasing cancer risk. In contrast to the original hypothesis that phosphate counteracts the effect of calcium, evidence has now been provided that phosphate is crucial for the intraluminal binding of bile acids in complexes of calcium, phosphate, and bile acids. Supplemental calcium has been shown to reduce the cytotoxic potential of fecal water, which is probably attributable to the profound effect of calcium on bile acid and fatty acid metabolism. However, some reservation with regard to the protective ability of calcium seems to be warranted as we found that oral calcium supplementation caused an increase in epithelial proliferation rate in the sigmoid of patients with adenomatous polyps. Further controlled studies evaluating the effects of calcium on the epithelium of different parts of the colon should now be performed.
Executive Subprocesses in Working Memory (2003)

A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environmental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition.