gebhart/patrepeval huggingface dataset:
Synchrotron crystallography (2000)

The past decade has seen an explosive growth in atomic-level structures determined by X-ray crystallography. Synchrotron radiation and a number of technical advances related quite directly to its development have fueled this growth. With the most recent advances coming to be used collectively and new resources being built, the foundation is laid for a dramatic further expansion of synchrotron crystallography in the next decade. Both the high-throughput applications of structural genomics and also the challenging studies of macromolecular machinery are expected to flourish.
Strategies for Discovering and Derisking Covalent, Irreversible Enzyme Inhibitors (2010)

This article presents several covalent inhibitors, including examples of successful drugs, as well as highly selective, irreversible inhibitors of emerging therapeutic targets, such as fatty acid amide hydolase. Covalent inhibitors have many desirable features, including increased biochemical efficiency of target disruption, less sensitivity toward pharmacokinetic parameters and increased duration of action that outlasts the pharmacokinetics of the compound. Safety concerns that must be mitigated include lack of specificity and the potential immunogenicity of protein-inhibitor adduct(s). Particular attention will be given to recent technologies, such as activity-based protein profiling, which allow one to define the proteome-wide selectivity patterns for covalent inhibitors in vitro and in vivo. For instance, any covalent inhibitor can, in principle, be modified with a 'clickable' tag to generate an activity probe that is almost indistinguishable from the original agent. These probes can be applied to any living system across a broad dose range to fully inventory their on and off targets. The substantial number of drugs on the market today that act by a covalent mechanism belies historical prejudices against the development of irreversibly acting therapeutic small molecules. Emerging proteomic technologies offer a means to systematically discriminate safe (selective) versus deleterious (nonselective) covalent inhibitors and thus should inspire their future design and development.
IMPRESSIONS OF A SCHOLARLY GENTLEMAN: PROFESSOR LOUIS GOLDBERG (1994)

This study presents a personal portrait of Emeritus Professor Louis Goldberg, a prominent founder of accounting education and research in the Australian academic community. It offers a distinctive view of Professor Goldberg through its employment of oral history research method. The data and findings presented herein are based on interviews with Professor Goldberg and both past and present academic colleagues. The paper reviews his formative years and his role as a professor and administrator, as well as teacher and researcher. Also documented are his perspectives on the education process and some of his own personal characteristics that have played a part in his academic career.
Mouse models for mitochondrial disease (2001)

Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes have been implicated in a wide range of neuromuscular diseases. MtDNA base substitution and rearrangement mutations generally inactivate one or more tRNA or rRNA genes and can cause myopathy, cardiomyopathy, cataracts, growth retardation, diabetes, etc. nDNA mutations can cause Leigh syndrome, cardiomyopathy, and nephropathy, due to defects in oxidative phosphorylation (OXPHOS) enzyme complexes; cartilage-hair hypoplasia (CHH) and mtDNA depletion syndrome, through defects in mitochondrial nucleic acid metabolism; and ophthalmoplegia with multiple mtDNA deletions, caused by adenine nucleotide translocator-1 (ANT1) mutations. Mouse models have been prepared that recapitulate a number of these diseases. The mtDNA 16S rRNA chloramphenicol (CAP) resistance mutation was introduced into the mouse female germline and caused cataracts and rod and cone abnormalities in chimeras and neonatal lethal myopathy and cardiomyopathy in mutant animals. A mtDNA deletion was introduced into the mouse germline and caused myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes. The ATP/ADP ratio was implicated in mitochondrial diabetes through transgenic modification of the beta-cell ATP-sensitive K(+) channel (K(ATP)). Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. Inactivation of uncoupler proteins (Ucp) 1-3 revealed that mitochondrial Delta Psi regulated ROS production. The role of mitochondrial ROS toxicity in disease and aging was confirmed by inactivating glutathione peroxidase (GPx1), resulting in growth retardation, and by total and partial inactivation of Mn superoxide dismutase (MnSOD; Sod2), resulting in neonatal lethal dilated cardiomyopathy and accelerated apoptosis in aging, respectively. The importance of mitochondrial ROS in degenerative diseases and aging was confirmed by treating Sod2 -/- mice and C. elegans with catalytic antioxidant drugs.
Bacterial Populations Contaminating The Upper Gut in Patients With Small Intestinal Bacterial Overgrowth Syndrome (1999)

Contaminating flora isolated in SIBOS include commonly identified oropharyngeal and colonic flora, but these occur in SIBOS at different levels from those usually found in their original location. These data may hopefully serve as a starting point to further therapeutic controlled studies.
Antibodies to poly[(2----8)-alpha-N-acetylneuraminic acid] and poly[(2----9)-alpha-N-acetylneuraminic acid] are elicited by immunization of mice with Escherichia coli K92 conjugates: potential vaccines for groups B and C meningococci and E. coli K1. (1991)

Meningitis and other systemic infections caused by group B Neisseria meningitidis and Escherichia coli K1 remain important problems. The capsular polysaccharides (CPs) of these pathogens (poly[(2----8)-alpha-N-acetylneuraminic acid] or poly(alpha 2-8NeuNAc] are identical and are virulence factors and protective antigens for both. CP vaccines for these pathogens are not available because poly(alpha 2-8NeuNAc) alone, as a complex or a conjugate, is poorly immunogenic. Because oligomers of poly(alpha 2-8NeuNAc) in fetal brain and other tissues bind antibodies in vitro, it has been suggested that antibodies to this CP might be pathologic. We synthesized conjugates of this CP with tetanus toxoid under conditions that avoid lactone formation. Using this scheme, we also synthesized conjugates of group C meningococcal CP (poly[(2----9)-alpha-N-acetylneuraminic acid] or poly(alpha 2-9NeuNAc] and of E. coli K92 CP [poly(alpha 2-8, alpha 2-9NeuNAc)]. When injected s.c. in saline into mice, conjugates of poly(alpha 2-8NeuNAc) or poly(alpha 2-9NeuNAc) elicited homologous antibodies. E. coli K92 conjugates elicited both poly(alpha 2-8NeuNAc) and poly(alpha 2-9NeuNAc) antibodies. Both components of the conjugates expressed T-dependent immunologic properties under conditions and dosages acceptable for clinical evaluation. Poly(alpha 2-8NeuNAc) antibodies elicited by the homologous or the K92 conjugates had lower binding activities at 37 degrees C than at 22 degrees C. "Natural" poly(alpha 2-8NeuNAc) antibodies were present in almost all matched pairs of human maternal and cord sera; most cord levels were higher than in corresponding maternal sera. These findings suggest that increased levels of poly(alpha 2-8NeuNAc) IgG antibodies elicited by our conjugates will confer protective immunity to group B meningococci and E. coli K1 and will not be pathologic.
The Value of Antibodies 44-3A6, SM3, HBME-1, and Thrombomodulin in Differentiating Epithelial Pleural Mesothelioma From Lung Adenocarcinoma (1997)

The distinction between pleural mesothelioma and peripheral pulmonary adenocarcinoma involving the pleura continues to be a diagnostic problem in surgical pathology. In recent years, the use of various immunohistochemical markers to facilitate this differential diagnosis has become common. In this study, the value of monoclonal antibodies 44-3A6, SM3, HBME-1, and thrombomodulin is compared in the differentiation of these conditions. Fifteen (68.2%) of 22, and 10 (52.6%) of 19 mesotheliomas stained positively with 44-3A6 and SM3, respectively, whereas all 23 (100%) adenocarcinomas reacted with both antibodies. Sixteen (80%) of 20 mesotheliomas and 14 (63.6%) of 22 lung adenocarcinomas reacted with HBME-1, whereas 16 (80%) of 20 mesotheliomas and only three (11.1%) of 27 adenocarcinomas were positive for thrombomodulin. Because thrombomodulin was expressed in most mesotheliomas but in only a few lung adenocarcinomas, this marker may have some diagnostic value when it is included in the standard immunohistochemical panel of markers used in the evaluation of mesotheliomas, especially when a positive marker for mesothelioma is needed. Antibodies 44-3A6, SM3, and HBME-1 have no practical value in discriminating epithelial pleural mesothelioma from lung adenocarcinoma.
IMGT Colliers de Perles: Standardized Sequence-Structure Representations of the IgSF and MhcSF Superfamily Domains (2007)

IMGT®, the international ImMunoGeneTics information system® (http://imgt.cines.fr) provides a common access to expertly annotated data on the genome, proteome, genetics and structure of immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC) of human and other vertebrates, and related proteins of the immune system (RPI) of any species. RPI include proteins that belong to the immunoglobulin superfamily (IgSF) and MHC superfamily (MhcSF). IMGT has set up a unique numbering system, which takes into account the structural features of the Ig-like and Mhc-like domains. In this paper, we describe the IMGT Scientific chart rules for the description of the IgSF V type and C type and of the MhcSF G type domains. These rules are based on the IMGT-ONTOLOGY concepts and are applicable for the sequence and structure analysis, whatever the species, the IgSF or MhcSF protein, or the chain type. We present examples of IMGT Colliers de Perles of IgSF V type (V-DOMAIN and V-LIKE-DOMAIN), C type (C-DOMAIN and C-LIKE-DOMAIN) and MhcSF G type (G-DOMAIN and G-LIKE-DOMAIN) based on the IMGT unique numbering. These standardized two-dimensional graphical representations are particularly useful for antibody engineering, sequence- structure analysis, visualization and comparison of positions for mutations, polymorphisms and contact analysis. Keywords: IMGT, immunoglobulin superfamily, major histocompatibility complex superfamily, domain alignment, Ig-like, Mhc-like
Primary structure of the herpesvirus saimiri genome (1992)

This report describes the complete nucleotide sequence of the genome of herpesvirus saimiri, the prototype of gammaherpesvirus subgroup 2 (rhadinoviruses). The unique low-G + C-content DNA region has 112,930 bp with an average base composition of 34.5% G + C and is flanked by about 35 noncoding high-G + C-content DNA repeats of 1,444 bp (70.8% G + C) in tandem orientation. We identified 76 major open reading frames and a set of seven U-RNA genes for a total of 83 potential genes. The genes are closely arranged, with only a few regions of sizable noncoding sequences. For 60 of the predicted proteins, homologous sequences are found in other herpesviruses. Genes conserved between herpesvirus saimiri and Epstein-Barr virus (gammaherpesvirus subgroup 1) show that their genomes are generally collinear, although conserved gene blocks are separated by unique genes that appear to determine the particular phenotype of these viruses. Several deduced protein sequences of herpesvirus saimiri without counterparts in most of the other sequenced herpesviruses exhibited significant homology with cellular proteins of known function. These include thymidylate synthase, dihydrofolate reductase, complement control proteins, the cell surface antigen CD59, cyclins, and G protein-coupled receptors. Searching for functional protein motifs revealed that the virus may encode a cytosine-specific methylase and a tyrosine-specific protein kinase. Several herpesvirus saimiri genes are potential candidates to cooperate with the gene for saimiri transformation-associated protein of subgroup A (STP-A) in T-lymphocyte growth stimulation.
BRAF Inhibitor Vemurafenib Improves the Antitumor Activity of Adoptive Cell Immunotherapy (2012)

Combining immunotherapy with targeted therapy blocking oncogenic BRAFV600 may result in improved treatments for advanced melanoma. In this study, we developed a BRAFV600E-driven murine model of melanoma, SM1, which is syngeneic to fully immunocompetent mice. SM1 cells exposed to the BRAF inhibitor vemurafenib (PLX4032) showed partial in vitro and in vivo sensitivity resulting from the inhibition of MAPK pathway signaling. Combined treatment of vemurafenib plus adoptive cell transfer therapy with lymphocytes genetically modified with a T-cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by SM1-OVA tumors or pmel-1 TCR transgenic lymphocytes recognizing gp100 endogenously expressed by SM1 resulted in superior antitumor responses compared with either therapy alone. T-cell analysis showed that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells. However, vemurafenib paradoxically increased mitogen-activated protein kinase (MAPK) signaling, in vivo cytotoxic activity, and intratumoral cytokine secretion by adoptively transferred cells. Taken together, our findings, derived from 2 independent models combining BRAF-targeted therapy with immunotherapy, support the testing of this therapeutic combination in patients with BRAFV600 mutant metastatic melanoma.
Rescue of noncultivatable human rotavirus by gene reassortment during mixed infection with ts mutants of a cultivatable bovine rotavirus. (1981)

Fastidious human rotaviruses that did not undergo productive infection in tissue culture were rescued by genetic reassortment during mixed infection with a temperature-sensitive (ts) mutant of a cultivatable bovine rotavirus. In this manner, the genes of the fastidious rotavirus that restricted growth in vitro were replaced by the corresponding genes from a tissue culture-adapted rotavirus. We recovered genetically reassorted viruses that grew to high titer and were neutralized specifically by hyperimmune guinea pig type 1 or type 2 human rotavirus antiserum. Preliminary RNA analysis of these clones disclosed that they were indeed viruses with reassorted genes.
Mutational Analysis of Immunoreceptor Tyrosine-Based Inhibition Motifs of the Ig-Like Transcript 2 (CD85j) Leukocyte Receptor (2002)

The inhibitory receptor Ig-like transcript (ILT)2 (leukocyte Ig-like receptor or CD85j) is a type I transmembrane protein expressed by different leukocyte lineages. The extracellular region of ILT2 binds HLA class I molecules, and its cytoplasmic domain displays four immunoreceptor tyrosine-based inhibition motifs. Upon tyrosine phosphorylation ILT2 recruits the Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) that is involved in negative signaling. To address the structural basis of ILT2-mediated inhibitory signaling, deletion and single tyrosine mutants were generated and transfected in the COS-7 and rat basophilic leukemia cell lines; their abilities to bind SHP-1 and to inhibit FcepsilonR-induced serotonin release in rat basophilic leukemia cells were studied. Both biochemical and functional analyses revealed tyrosines 644 (SIYATL) and 614 (VTYAQL) as the SHP-1 docking sites required for ILT2 inhibitory function. Substitution of tyrosine 562 (VTYAEV) did not alter receptor function. By contrast, mutation of tyrosine 533 (NLYAAV) interfered with ILT2 tyrosine phosphorylation and the subsequent SHP-1 recruitment, thus supporting a regulatory role for this motif.
Erratum: Mechanism of Inactivation of Enzyme Proteins by Ultraviolet Light (1961)

In the article Radio telemetering from within the body by R. Stuart Mackay [ Science 134, 1196 (20 Oct. 1961)] one line was omitted and another line was printed twice in the paragraph beginning just above the middle of column 1, page 1199. first line of the paragraph is repeated in the fourth line. first two sentences should have read: The permissible radio-frequency deviation is limited to the bandwidth of the receiver if loss of signal is never to occur. Receivers can record higher-deviation signals by tracking them with a standard automatic frequency-control circuit, the frequency-discriminator signal then being the useful output (8)(italicized words omitted).
Development of an intracellular pool of glucose transporters in 3T3-L1 cells. (1992)

The membrane-impermeant bis-mannose photolabel 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis-(D-mannos- 4-yloxy)-2- propylamine (ATB-BMPA) has been used to study the development of an intracellular pool of glucose transporters in 3T3-L1 cells. The subcellular distributions of the transporter isoforms GLUT1 and GLUT4 were determined by comparing the labeling obtained in cells in which the impermeant reagent only had access to the cell surface and the labeling obtained in digitonin-permeabilized cells. ATB-BMPA labeling showed that only GLUT1 was present in preconfluent fibroblasts and that most of the transporters were distributed to the cell surface. In preconfluent fibroblasts, the 2-deoxy-D-glucose transport activity was approximately 5 times higher than in confluent fibroblasts. ATB-BMPA labeling showed that the decrease in transport as cells reached confluence was associated with a decrease in the proportion of GLUT1 distributed to the cell surface. The sequestration of these transporters was associated with the development of an insulin-responsive transport activity which increased by approximately 2.5-fold compared with unstimulated confluent cells. ATB-BMPA labeling showed that insulin stimulation resulted in an approximately 2-fold increase in surface GLUT1 so that about one-half of the available transporters became recruited to the cell surface. Measurements of the changes in the distribution of both GLUT1 and GLUT4 throughout the differentiation of confluent fibroblasts into adipocytes showed that both transporters were sequestered in parallel. Basal levels of transport and photolabeling remained low throughout the differentiation period when the total pool of transporters (GLUT1 plus GLUT4) was increased by approximately 5-fold. These results suggest that the sequestration process was present before new transporters were synthesized. Thus, the sequestration mechanism develops in confluent growth-arrested fibroblasts although the capacity to sequester additional transporters may increase as differentiation proceeds.
Monoclonal antibody SN2 defining a human T cell leukemia-associated cell surface glycoprotein. (1984)

We generated a monoclonal antibody, termed SN2, which defines a human T cell leukemia-associated cell surface glycoprotein, GP37, with an approximate m.w. of 37,000. This antibody was generated by using a human leukemia antigen preparation. The reactivity and specificity of SN2 were characterized by a sensitive radioimmunoassay against a variety of cultured and uncultured human cells. In selected cases, the cell specimens were tested further by indirect immunofluorescence staining. Among the various cultured malignant and nonmalignant human cell lines tested, SN2 reacted only with leukemic T cell lines, with one exception. It reacted with 10 of 11 leukemic T cell lines tested; the 10 reactive cell lines are PEER, JM, MOLT-4, CCRF-CEM, CCRF-H-SB2, RPMI 8402, DND-41, HPB-ALL, SKW-3, and HPB-MLT; the unreactive line was HUT 78. The reactive cell lines were derived from patients either with T cell-type acute lymphoblastic leukemia (the first eight cell lines), with T cell chronic lymphocytic leukemia (SKW-3), or with Japanese adult T cell leukemia-lymphoma (HPB-MLT). The unreactive cell line, HUT 78, was from a patient with Sezary syndrome. Results consistent with the above were obtained from studies in which uncultured malignant cell specimens from different cancer patients were tested against SN2; SN2 reacted only with T leukemia cells. Among various uncultured normal cell specimens tested, SN2 did not react with thymocytes, bone marrow cells, peripheral blood lymphocytes containing B and T cells, purified T cells, monocytes, granulocytes, or erythrocytes. It did, however, react with platelets.
Characterization of a Chimeric T-Cell Receptor with Specificity for the Hodgkin??s Lymphoma-Associated CD30 Antigen (1999)

Recombinant receptors with antibody-like specificity for tumor-associated antigens were shown to direct specifically T cells to target tumor cells. Hodgkin and Reed-Sternberg cells, the malignant cell population in Hodgkin's lymphoma, express high amounts of the cell surface antigen CD30. An anti-CD30 T-cell receptor with cellular activation properties is expected to graft T cells with specificity to Hodgkin cells. Here, the authors characterize a chimeric T-cell receptor with an extracellular domain consisting of the single-chain antibody fragment HRS3-scFv with specificity for the CD30 antigen and intracellular domain of the signal transducing part of the Fc-epsilon-I-gamma receptor. The HRS3-scFv was derived from the monoclonal anti-CD30 antibody HRS3 and retained specificity for the CD30 antigen. The recombinant HRS3-scFv-gamma receptor was expressed under control of the RSV-LTR after transfection into MD45 T-cells. The chimeric receptor protein is detected and analyzed by enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation. Expression of the chimeric receptor converts MD45 T cells to specificity for CD30+ lymphoma cells. Specific cross-linking of the chimeric receptor with antigen resulted in cytolytic reactivity against CD30+ tumor cells in vitro. The results demonstrate that the chimeric receptor HRS3-scFv-gamma converts T cells to a specific MHC-unrestricted cytolytic response against CD30+ tumor cells offering an alternative strategy in cellular immunotherapy of Hodgkin's disease.
In-vitro studies of diclofenac sodium controlled-release from biopolymeric hydrophilic matrices. (2003)

The release of Diclofenac Sodium was influenced by the presence of MCC, and by the different concentrations of starch and lactose. Drug release kinetics from these formulations corresponded best to the zero-order kinetics. Compared to conventional tablets, release of the model drug from these HPMC matrix tablets was prolonged; as a result, an oral release dosage form to avoid the gastrointestinal adverse effects was achieved.
Analysis of the VNTR locus D1S80 by the PCR followed by high-resolution PAGE. (1991)

Allelic data for the D1S80 locus was obtained by using the PCR and subsequent analysis with a high-resolution, horizontal PAGE technique and silver staining. Compared with RFLP analysis of VNTR loci by Southern blotting, the approach described in this paper offers certain advantages: (1) discrete allele resolution, (2) minimal measurement error, (3) correct genotyping of single-band VNTR patterns, (4) a nonisotopic assay, (5) a permanent record of the electrophoretic separation, and (6) reduced assay time. In a sample of 99 unrelated Caucasians, the D1S80 locus demonstrated a heterozygosity of 80.8% with 37 phenotypes and 16 alleles. The distribution of genotypes is in agreement with expected values according to the Hardy-Weinberg equilibrium. Furthermore, the observed number of alleles and the level of heterozygosity, obtained through the protocol described here, were congruent with each other in accordance with the expectation of a mutation-drift equilibrium model for a single, homogeneous, random-mating population. Therefore, the analysis of D1S80 and similar VNTR loci by amplified fragment length polymorphism (AMP-FLP) may prove useful as models for population genetic issues for VNTR loci analyzed by RFLP typing via Southern blotting.