gebhart/patrepeval huggingface dataset:
The Role of Arsenic-Thiol Interactions in Metalloregulation of the ars Operon (1996)

The ars operon of the Escherichia coli plasmid R773 that confers arsenical and antimonial resistance is negatively regulated by the ArsR repressor. ArsR residues Cys-32 and Cys-34 were previously identified as involved in induction by arsenite and antimonite, suggesting coordination between As(III) and the two cysteine thiolates. However, in small molecule thiolate-As(III) complexes, arsenic is frequently three-coordinate. A site-directed mutagenic approach was employed in a search for a third arsenic ligand. ArsR proteins with C32G, C34G, and C32G/C34G substitutions were active repressors, but were not inducible in vivo. In vitro, the altered repressor-ars DNA complexes could not be dissociated by inducers. Alteration of Cys-37 and Ser-43, residues located in or near the putative helix-turn-helix DNA-binding region of the protein, had no effect on the inducibility of the operon. While these results indicated that neither the thiolate of Cys-37 nor the hydroxyl oxygen of Ser-43 is required for induction, they did not eliminate either atom as a potential arsenic ligand. Another approach involved reaction with an alternative inducer, phenylarsine oxide, which can form only two coordinations. Phenylarsine oxide was shown to be as effective as or more effective than arsenite or antimonite in induction in vivo. In vitro, the organic arsenical was more effective than either arsenite or antimonite in dissociating the repressor-promoter complex. Thus, two ArsR-arsenic bonds are sufficient for induction. The interaction of ArsR proteins with As(III) was examined using a phenylarsine oxide affinity resin. ArsR proteins containing any two of the three cysteine residues Cys-32, Cys-34, and Cys-37 bound to the resin. Alteration of any two of the three resulted in loss of binding. Arsenic X-ray absorption spectroscopy of ArsR treated stoichiometrically with arsenite confirmed the average arsenic coordination as AsS3 These results suggest that all three cysteine thiolates are arsenic ligands, but binding to only two, the Cys-32 and Cys-34 thiolates, is required to produce the conformational change that results in release of the repressor from the DNA and induction.
Effect of endurance training on glucose kinetics during exercise (1983)

Control and endurance-trained rats received continuous infusions via jugular catheters of [U-14C]- and [6-3H]glucose under one of three conditions: rest (Re), running at 13.4 m/min (easy exercise, EE), or running at 26.8 m/min (hard exercise, HE). Arterial blood was sampled from carotid catheters. Blood glucose levels were not different between groups at rest (3.88 +/- 0.19 mM) or EE (4.32 +/- 0.35 mM). During HE, trained animals maintained blood glucose better (3.41 +/- 0.34 mM) than did untrained animals (3.03 +/- 0.42 mM). Respiratory exchange ratio (R) increased from rest (0.79 +/- 0.05) to exercise and was significantly lower in trained than in untrained animals during HE (0.87 +/- 0.02 vs. 0.93 +/- 0.03). Glucose turnover (Rt) calculated from [3H]glucose was not different between groups at rest (46.2 +/- 2.7 mumol x kg-1 x min-1). Turnover increased during EE to 91.5 +/- 7.5 vs. 72 +/- 8.5 mumol x kg-1 x min-1 in untrained and trained animals, respectively. During HE, Rt rose to 95.0 +/- 12.6 in trained animals but fell to 78.7 +/- 9.9 mumol x kg-1 x min-1 in untrained animals. The percentage of glucose flux oxidized increased from rest (44.0 +/- 6.8%) to exercise and was significantly lower in trained (73.7 +/- 4.3%) than in untrained animals (95.1 +/- 3.8%) during HE. Metabolic clearance rate increased from 12.5 +/- 0.8 in Re to 29.4 +/- 6.0 ml x min-1 x kg-1 in HE but did not differ between groups. Training improved glucose homeostasis during HE by increasing the glucose flux and by reducing the fraction of the flux lost to oxidation.
707-AP peptide recognized by human antibody induces human leukocyte antigen A2-restricted cytotoxic T lymphocyte killing of melanoma. (1997)

We recently identified a tumor-associated antigen that was recognized by human monoclonal antibody L94. The antibody-reactive 707-AP sequence RVAALARDAP, cloned from a melanoma cDNA library, was also found to be recognized by peripheral blood lymphocytes (PBLs) from melanoma patients. In this study, 707-AP was used to stimulate melanoma patients' PBLs for the establishment of peptide-specific CTL cell lines. CTL cell lines derived from 258 melanoma patients of different human leukocyte antigen (HLA)-A and HLA-B allele expressions were assessed by a 51Cr cytotoxicity assay against the peptide-pulsed autologous B lymphoblastoid cells and T2 HLA-A2 antigen-presenting cells and autologous and allogeneic melanoma cell lines. The analysis of 707-AP CTL activity demonstrated that only HLA-A2 patients' PBLs could be stimulated with 707-AP. 707-AP CTLs were able to specifically lyse HLA-A2 autologous and allogeneic melanoma cell lines. This verified the endogenous processing and presentation of 707-AP by melanoma cells. 707-AP CTL cytotoxicity against peptide-pulsed autologous HLA-A2 B lymphoblastoid cells and T2 HLA-A2 cells was also demonstrated. The killing activity of HLA-A2 707-AP CTL cell lines (CD8+ CD3+) was inhibited by anti-HLA class and anti-HLA-A2 monoclonal antibodies. The amino acid substitution or deletion analysis of the 707-AP sequence in CTL stimulation and recognition confirmed that position 2, amino acid V and position 9, amino acid A were essential. Both positions are known as supermotif anchors for HLA-A2 peptide sequences. Our studies demonstrated that 707-AP is a potent stimulator of CTLs that can induce peptide-specific HLA-A2 melanoma cell killing. The recognition of 707-AP by both antibody and CTLs suggests its potential significance as a peptide immunotherapeutic.
Complete Complement Components C4A and C4B Deficiencies in Human Kidney Diseases and Systemic Lupus Erythematosus (2004)

Although a heterozygous deficiency of either complement component C4A or C4B is common, and each has a frequency of approximately 20% in a Caucasian population, complete deficiencies of both C4A and C4B proteins are extremely rare. In this paper the clinical courses for seven complete C4 deficiency patients are described in detail, and the molecular defects for complete C4 deficiencies are elucidated. Three patients with homozygous HLA A24 Cw7 B38 DR13 had systemic lupus erythematosus, mesangial glomerulonephritis, and severe skin lesions or membranous nephropathy. Immunofixation, genomic restriction fragment length polymorphisms, and pulsed field gel electrophoresis experiments revealed the presence of monomodular RP-C4-CYP21-TNX (RCCX) modules, each containing a solitary, long C4A mutant gene. Sequencing of the mutant C4A genes revealed a 2-bp, GT deletion in exon 13 that leads to protein truncation. The other four patients with homozygous HLA A30 B18 DR7 had SLE, severe kidney disorders including mesangial or membranoproliferative glomerulonephritis, and/or Henoch Schoenlein purpura. Molecular genetic analyses revealed an unusual RCCX structure with two short C4B mutant genes, each followed by an intact gene for steroid 21-hydroxylase. Nine identical, intronic mutations were found in each mutant C4B. In particular, the 8127 g-->a mutation present at the donor site of intron 28 may cause an RNA splice defect. Analyses of 12 complete C4 deficiency patients revealed two hot spots of deleterious mutations: one is located at exon 13, the others within a 2.6-kb genomic region spanning exons 20-29. Screening of these mutations may facilitate epidemiologic studies of C4 in infectious, autoimmune, and kidney diseases.
Activation of human monocytes through CD40 induces matrix metalloproteinases (1996)

The activation of monocytes/macrophages to secrete pro-inflammatory cytokines and matrix metalloproteinases (MMPs) is critically important in the development of chronic inflammatory diseases. However, the consequence of interactions between activated T cells and monocytes in these inflammatory processes is not well understood. In this study we have investigated the induction of MMPs in human monocytes by activated T cells. We show that fixed cells and the cell membranes from a T cell line, BMS-2, that expresses high levels of the CD40 ligand gp39 (also called TRAP, TBAM, or CD40L) stimulate both the expression of mRNA and the production of MMPs by human monocytic cells. Activation of monocytes by the human T cells could be significantly inhibited by a F(ab')2 fragment of a neutralizing Ab specific for human gp39, but not by an Ab that recognizes murine gp39. Furthermore, recombinant soluble gp39 (sgp39) alone induced marked increases in the levels of a 92-kDa metalloproteinase (gelatinase) in both the human monocytic cell line, THP-1, and peripheral human monocytes, and induction was blocked by the anti-human gp39 Ab. Pretreatment with IFN-gamma significantly enhanced gp39 induction of MMPs in THP-1 cells but not in peripheral monocytes. Up-regulation of mRNA for the 92-kDa MMP by gp39 could be detected within 6 h of stimulation and was maximal 24 h after treatment. MMP enzymatic activity was detectable in the culture medium 12 to 18 h following stimulation of the cells and remained high through 48 h. These results suggest the interaction of T cells with monocytes/macrophages via the gp39-CD40 counter receptors may be significant in development or maintenance of chronic inflammatory lesions.
Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2rγnullhumanized mice (2010)

Whereas humanized mouse models have contributed significantly to human immunology research, human T cells developing in mouse thymic environment fail to demonstrate HLA-restricted function. To achieve HLA-restricted human immune response, we created an immune-compromised non-obese diabetic/SCID/IL2rg(null) strain (NSG) with homozygous expression of HLA class I heavy chain and light chain (NSG-HLA-A2/HHD). Transplantation of purified Lin-CD34+CD38- human hematopoietic stem cells into NSG-HLA-A2/HHD newborns resulted in the development of human CD4+ and CD8+ TCR alphabeta+ T cells and CD4-CD8- and CD8+ TCR gammadelta+ cells in recipient bone marrow and spleen. Human cytotoxic T lymphocytes (CTLs) become functionally mature, as evidenced by the production of granzyme corresponding to phenotypic transition from naïve to effector memory CTLs. In these recipients, human Th17 cells developed along with Th1 and Th2 cells. Epstein-Barr virus (EBV) infection in the humanized NSG-HLA-A2/HHD recipients resulted in the formation of lymphoproliferative lesions consisting mainly of human B cells with scattered human T cells. Human CTLs developing in the recipients recognized EBV-derived peptides in an HLA-restricted manner and exerted HLA-restricted cytotoxicity against EBV-infected human B cells. The HLA-expressing humanized mouse with functional HLA-restricted T cells and consistent representation of rare T-cell subsets overcomes a major constraint in human immunology, and serves as a useful model for investigation of human immune responses against pathogens and for the development of therapeutic strategies against human diseases.
Hepatic stellate cells contribute to progenitor cells and liver regeneration (2014)

Retinoid-storing hepatic stellate cells (HSCs) have recently been described as a liver-resident mesenchymal stem cell (MSC) population; however, it is not clear whether these cells contribute to liver regeneration or serve as a progenitor cell population with hepatobiliary characteristics. Here, we purified HSCs with retinoid-dependent fluorescence-activated cell sorting from eGFP-expressing rats and transplanted these GFP(+) HSCs into wild-type (WT) rats that had undergone partial hepatectomy in the presence of 2-acetylaminofluorene (2AAF) or retrorsine, both of which are injury models that favor stem cell-based liver repair. Transplanted HSCs contributed to liver regeneration in host animals by forming mesenchymal tissue, progenitor cells, hepatocytes, and cholangiocytes and elevated direct bilirubin levels in blood sera of GUNN rats, indicating recovery from the hepatic bilirubin-handling defect in these animals. Transplanted HSCs engrafted within the bone marrow (BM) of host animals, and HSC-derived cells were isolated from BM and successfully retransplanted into new hosts with injured liver. Cultured HSCs transiently adopted an expression profile similar to that of progenitor cells during differentiation into bile acid-synthesizing and -transporting hepatocytes, suggesting that stellate cells represent a source of liver progenitor cells. This concept connects seemingly contradictory studies that favor either progenitor cells or MSCs as important players in stem cell-based liver regeneration.
Hypercoagulability in acute stroke (1987)

To evaluate the clinical significance of hemostatic abnormalities in acute stroke, we studied coagulation and platelet function in 70 patients with recent cerebral infarction or hemorrhage and in 45 age-matched controls. Higher levels of one-stage factor VIII coagulant activity, fibrinopeptide A (FPA), and beta-thromboglobulin were associated with the occurrence of stroke. All hemostatic test results were remarkably similar in patients with ischemic and hemorrhagic stroke. FPA levels and size of the lesion on CT were the only variables independently predicting mortality in a multivariate regression analysis. Our findings demonstrate that hypercoagulability is an important prognostic factor in stroke and lend support to clinical trials of drugs interfering with the coagulation system in the early phase of cerebral ischemia.
Lantadenes and Their Esters as Potential Antitumor Agents (2008)

Lantadenes are pentacyclic triterpenoids of the weed Lantana camara. Five new lantadenes (14-18) and their methyl esters (20-24) were synthesized, characterized, and screened for cytotoxicity against four human cancer cell lines. The parent compound (1) and the four most active compounds (15, 16, 21, and 22) were further studied for their in vivo tumor inhibitory potential on squamous cell carcinogenesis in Swiss albino mice induced by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). These results were supported by histopathological studies and discussed in terms of structure-activity relationships. The results inferred the importance of the groups attached to C-22 and C-17 in relation to the antitumor activity of these compounds.
New York in Store (2007)

Here is a quirky look at one hundred of New York's offbeat shops and shop windows. The businesses featured range from such Manhattan mainstays as Macy's and Katz's Delicatessen to the idiosyncratic, including the 99' store on East 14th Street, or Dr Rico Perez's drugstore in the Bronx. At a time when much of New York is succumbing to the uniformity of the mall and the ubiquity of the chainstore, this book is a precious record of the shops that are bucking the trend.
The Activation of Carbon−Chlorine Bonds in Per- and Polyfluoroalkyl Chlorides:  DMSO-Induced Hydroperfluoroalkylation of Alkenes and Alkynes with Sodium Dithionite (1999)

In DMSO, the addition reactions of perfluoroalkyl chlorides, R(F)Cl, to alkenes or alkynes can occur smoothly in the presence of 1.5 equiv of Na(2)S(2)O(4) and NaHCO(3) at 75-80 degrees C for 4-10 h to give the corresponding adducts (RCH(2)CH(2)R(F) or RCH=CHR(F)). Ethyl chlorofluoro- (1f), chlorodifluoro- (1g) acetates, even nonfluorinated compounds, such as ethyl dichloro- (1h), chloro- (1i) acetates, and chloroform (1j) can undergo the similar reaction. Treatment of omega-iodo (or chloro-) perfluoroalkyl chlorides [X(CF(2))(n)()Cl, n = 2, 4, X= I or Cl] with >3 equiv of alkenes and Na(2)S(2)O(4) gives directly the symmetrically disubstituted alkanes (RCH(2)CH(2))(2)(CF(2))(n)(). The symmetrically and unsymmetrically disubstituted adducts RCH(2)CH(2)(CF(2))(n)()CH(2)CH(2)R' from omega- iodoperfluoroalkyl chlorides can be also obtained stepwise, i.e., through the further addition reactions of monoadducts, RCH(2)CH(2)(CF(2))(n)()Cl to olefins. However, for alpha,omega-dichloroperfluoroalkanes, the similarly stepwise reactions with an alkene is not clean, both bis-adducts and the corresponding omega-hydrides, RCH(2)CH(2)(CF(2))(n)()H as byproducts are also formed. In the absence of alkenes or alkynes, per- and polyfluoroalkyl chlorides can be converted to their sulfinate salts and sulfonyl chlorides.
A Role for Noradrenergic Transmission in the Actions of Phencyclidine and the Antipsychotic and Antistress Effects of mGlu2/3 Receptor Agonists (2003)

Evidence suggests that glutamatergic neuronal transmission is involved in psychiatric and neurological disorders and that drugs that target glutamate systems may serve as novel therapeutics in humans. For example, agonists for group II mGlu receptors (mGlu2 and mGlu3) have been shown to be anxiolytic in certain animal models and have shown promise in early human trials. mGlu2/3 receptor agonists also block the neurochemical and behavioral actions of psychotogens, such as phencyclidine and amphetamine in rodents, suggesting that they may be useful to treat psychosis in humans. Recently, we have used in vivo microdialysis and behavioral methods to further explore the potential antipsychotic and antistress actions of mGlu2/3 receptor agonists in rats. In subjects undergoing brain microdialysis of the nucleus accumbens shell, we have shown that LY379268 (3 mg/kg s.c.) (a systemically active mGlu2/3 receptor agonist) blocks PCP-induced locomotor activations for approximately 3 hours. In these animals, PCP-induced dopamine release was reduced, but only in a transient fashion (15-75 min). PCP-induced norepinephrine release was also reduced, but unlike dopamine, in a manner that was temporally correlated with the reduction of PCP-induced behaviors. In separate experiments in rats not undergoing microdialysis, the alpha2-adrenergic receptor agonist, clonidine, was shown to block PCP behaviors, and the norepinephrine reuptake inhibitor reboxetine was shown to exacerbate PCP-induced ambulations. In the latter study, LY379268 pretreatment effectively reversed the PCP behaviors in both control and reboxetine-treated animals. These data support a role for noradrenergic neurotransmission in the actions of drugs such as phencyclidine and suggest that stress pathways associated with these drugs can be normalized by mGlu2/3 receptor activation.
Comparison of Natural Course, Intravitreal Triamcinolone, and Intravitreal Bevacizumab for Treatment of Macular Edema Secondary to Branch Retinal Vein Occlusion (2012)

Although IVTA and IVB were effective to decrease the macular edema at 1 month after the injection in BRVO. BCVA and CMT of the natural course group were not inferior to both the IVTA and the IVB groups at 12 months.
TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions (2013)

TopHat is a popular spliced aligner for RNA-sequence (RNA-seq) experiments. In this paper, we describe TopHat2, which incorporates many significant enhancements to TopHat. TopHat2 can align reads of various lengths produced by the latest sequencing technologies, while allowing for variable-length indels with respect to the reference genome. In addition to de novo spliced alignment, TopHat2 can align reads across fusion breaks, which can occur after genomic translocations. TopHat2 combines the ability to identify novel splice sites with direct mapping to known transcripts, producing sensitive and accurate alignments, even for highly repetitive genomes or in the presence of pseudogenes. TopHat2 is available at http://ccb.jhu.edu/software/tophat.
The effect of strain-induced band-gap narrowing on high concentration phosphorus diffusion in silicon (1979)

A strain effect has been found to explain the anomalous reduction in P diffusivity at surface concentrations greater than ∼4×1020 cm−3. It is shown that at diffusion temperatures, misfit-induced strain causes a reduction in the effective Si band gap up to ∼−130 meV at the solubility limit of P. This band-gap narrowing results in reduced P diffusivity through a relative reduction of P+V= pairs in the surface region. This complex is the dominant species for P transport at high P concentrations. The diffusion of P in the tail region is dominated by V− vacancies liberated during P+V= pair dissociation events. Thus, the tail diffusivity will likewise be reduced by band-gap narrowing in the surface region. These reductions in diffusivity can be by as much as a factor of 6 depending upon temperature and P doping.
Harnessing Chaperones to Generate Small-Molecule Inhibitors of Amyloid ß Aggregation (2004)

Protein aggregation is involved in the pathogenesis of neurodegenerative diseases and hence is considered an attractive target for therapeutic intervention. However, protein-protein interactions are exceedingly difficult to inhibit. Small molecules lack sufficient steric bulk to prevent interactions between large peptide surfaces. To yield potent inhibitors of beta-amyloid (Abeta) aggregation, we synthesized small molecules that increase their steric bulk by binding to chaperones but also have a moiety available for interaction with Abeta. This strategy yields potent inhibitors of Abeta aggregation and could lead to therapeutics for Alzheimer's disease and other forms of neurodegeneration.
Methylation of Catechol Estrogen with Diazomethane (1983)

Dynamic aspects of methylation of catechol estrogen with diazomethane were investigated by means of thin-layer chromatography. The methylation rate of the hydroxyl group at the C-3 position was almost the same as that of the C-2 hydroxyl group in the reaction of 2-hydroxyestrogen, and 2-3 times that of the C-4 hydroxyl group in the reaction of 4-hydroxyestrogen. In these experiments, the maximum yields of 2-methoxyestrone, 2-hydroxyestrone 3-methyl ether, 4-methoxyestrone and 4-hydroxyestrone 3-methyl ether were 32, 39, 13 and 70%, respectively. In addition, demethylation of catechol estrogen dimethyl ethers with boron tribromide and synthesis of 4-hydroxyestrone monomethyl ethers are described.
U.S. Food and Drug Administration Approval Summary: Brentuximab Vedotin for the Treatment of Relapsed Hodgkin Lymphoma or Relapsed Systemic Anaplastic Large-Cell Lymphoma (2012)

The U.S. Food and Drug Administration (FDA) describes the accelerated approval of brentuximab vedotin for patients with relapsed Hodgkin lymphoma and relapsed systemic anaplastic large-cell lymphoma (sALCL). FDA analyzed the results of two single-arm trials, enrolling 102 patients with Hodgkin lymphoma and 58 patients with sALCL. Both trials had primary endpoints of objective response rate (ORR) and key secondary endpoints of response duration and complete response (CR) rate. For patients with Hodgkin lymphoma, ORR was 73% (95% CI, 65-83%); median response duration was 6.7 months, and CR was 32% (95% CI, 23-42%). For patients with sALCL, ORR was 86% (95% CI, 77-95%), median response duration was 12.6 months, and CR was 57% (95% CI, 44-70%). The most common adverse reactions were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. FDA granted accelerated approval of brentuximab vedotin for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of patients with sALCL after failure of at least one prior multiagent chemotherapy regimen.