gebhart/patrepeval huggingface dataset:
Sex Steroids and Bone (2002)

The adult skeleton is periodically remodeled by temporary anatomic structures that comprise juxtaposed osteoclast and osteoblast teams and replace old bone with new. Estrogens and androgens slow the rate of bone remodeling and protect against bone loss. Conversely, loss of estrogen leads to increased rate of remodeling and tilts the balance between bone resorption and formation in favor of the former. Studies from our group during the last 10 years have elucidated that estrogens and androgens decrease the number of remodeling cycles by attenuating the birth rate of osteoclasts and osteoblasts from their respective progenitors. These effects result, in part, from the transcriptional regulation of genes responsible for osteoclastogenesis and mesenchymal cell replication and/or differentiation and are exerted through interactions of the ligand-activated receptors with other transcription factors. However, increased remodeling alone cannot explain why loss of sex steroids tilts the balance of resorption and formation in favor of the former. Estrogens and androgens also exert effects on the lifespan of mature bone cells: pro-apoptotic effects on osteoclasts but anti-apoptotic effects on osteoblasts and osteocytes. These latter effects stem from a heretofore unexpected function of the classical "nuclear" sex steroid receptors outside the nucleus and result from activation of a Src/Shc/extracellular signal-regulated kinase signal transduction pathway probably within preassembled scaffolds called caveolae. Strikingly, estrogen receptor (ER) alpha or beta or the androgen receptor can transmit anti-apoptotic signals with similar efficiency, irrespective of whether the ligand is an estrogen or an androgen. More importantly, these nongenotropic, sex-nonspecific actions are mediated by the ligand-binding domain of the receptor and can be functionally dissociated from transcriptional activity with synthetic ligands. Taken together, these lines of evidence strongly suggest that, in sex steroid deficiency, loss of transcriptional effects may be responsible for the increased osteoclastogenesis and osteoblastogenesis and thereby the increased rate of bone remodeling. Loss of nongenotropic anti-apoptotic effects on mature osteoblasts and osteocytes, in combination with an opposite effect on the lifespan of mature osteoclasts, may be responsible for the imbalance between formation and resorption and the progressive loss of bone mass and strength. Elucidation of the dual function of sex steroid receptors has important pathophysiologic and pharmacologic implications. Specifically, synthetic ligands of the ER that can evoke the nongenotropic but not the genotropic signal may be bone anabolic agents, as opposed to natural estrogens or selective estrogen receptor modulators that are antiresorptive agents. The same ligands may also circumvent the side effects associated with conventional hormone replacement therapy.
Multiplex PCR Assay for Simultaneous Detection of Nine Clinically Relevant Antibiotic Resistance Genes inStaphylococcus aureus (2003)

In this study we describe a multiplex PCR assay for the detection of nine clinically relevant antibiotic resistance genes of Staphylococcus aureus. Conditions were optimized to amplify fragments of mecA (encoding methicillin resistance), aacA-aphD (aminoglycoside resistance), tetK, tetM (tetracycline resistance), erm(A), erm(C) (macrolide-lincosamide-streptogramin B resistance), vat(A), vat(B), and vat(C) (streptogramin A resistance) simultaneously in one PCR amplification. An additional primer pair for the amplification of a fragment of the staphylococcal 16S rDNA was included as a positive control. The multiplex PCR assay was evaluated on 30 different S. aureus isolates, and the PCR results correlated with the phenotypic antibiotic resistance data obtained by the broth microdilution assay. The multiplex PCR assay offers a rapid, simple, and accurate identification of antibiotic resistance profiles and could be used in clinical diagnosis as well as for the surveillance of the spread of antibiotic resistance determinants in epidemiological studies.
Improved Ruthenium‐Catalyzed Amination of Alcohols with Ammonia: Synthesis of Diamines and Amino Esters (2011)

Diamination of diols: The first homogeneously catalyzed diaminations of primary and secondary diols with ammonia give the corresponding diamines. Other primary as well as secondary alcohols including hydroxy-substituted esters can also be efficiently converted to primary amines. This atom-efficient and selective amination method proceeds in an ammonia atmosphere without additional hydrogen sources. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Significance of Quantitative Salivary Cultures for Group A and Non-group A β-Hemolytic Streptococci in Patients with Pharyngitis and in Their Family Contacts (1979)

One hundred ninety-six individuals, 86 with clinically overt pharyngotonsillitis and 110 of their clinically negative contacts were studied to evaluate the sensitivity and the specificity of quantitative saliva cultures for group A β-hemolytic streptococci. We also compared this technique with semiquantitative throat cultures as a means of isolating group A streptococci and of differentiating the streptococcal carrier state from patients with bona fide streptococcal upper respiratory tract infection as defmed by the presence of an antibody response. The data indicate that the throat culture is a more reliable means of identifying group A β-hemolytic streptococci in the upper respiratory tract than is the saliva culture. The converse is true for non-group A β-hemolytic streptococci; the saliva culture is a much better means for isolating these organisms. In individuals positive by both techniques we found good correlation between the degree of positivity of the saliva culture and the degree of positivity of the throat culture. Furthermore, while there was a definite trend for individuals with strongly positive cultures to demonstrate more often an antibody rise in either antistreptolysin O and/or antideoxynibonuclease B—indicating bona fide infection—this relationship was not sufficiently constant to provide a clear differentiation. This study also indicates that discordance (one positive, one negative) of simultaneous duplicate semiquantitative throat cultures is much more common among individuals who do not show an antibody response ("carriers") than among those with an antibody response (bona fide infection). This study confirms our previous observations suggesting that the presence of C-reactive protein in the serum of patients with a positive culture for group A streptococci and clinical signs and symptoms of pharyngitis is often an indication of true streptococcal upper respiratory tract infection, and that even with a positive saliva culture at the initial visit, a negative C-reactive protein is only infrequently (25%) associated with an antibody response.
Newly Identified Actions of the Vitamin D Endocrine System* (1992)

VITAMIN D is a seco-steroid in which the B-ring of the cyclopentanoperhydrophenanthrene structure is cleaved. The vitamin is either obtained from the diet or is synthesized in the skin from 7-dehydrocholesterol (Fig. 1) and is itself biologically inert (for reviews see Refs. 1–8). Vitamin D and its metabolites circulate in the blood primarily bound to and in equilibrium association with the vitamin D-binding globulin [DBP]. In the liver, the enzyme 25-hydroxylase converts the vitamin to the inactive hormonal precursor 25-hydroxyvitamin D [25(OH)D]. Subsequently, the renal lα-hydroxylase enzyme converts 25(OH)D to the biologically active form 1,25-dihydroxyvitamin D [1,25(OH)2D]. Both hydroxylase enzymes are cytochrome P450-containing enzymes. la-Hydroxylase activity is tightly controlled by a number of ionic and endocrine factors including stimulation by PTH and reduced plasma Ca2+ or inhibition by 1,25(OH)2D in a classic negative feedback loop. Although not illustrated in Fig. 1, under conditions of adequate plasma Ca2+ levels, 25(OH)D is alternatively converted to 24,25(OH)2D by the reciprocally regulated renal P450- dependent 24-hydroxylase enzyme. Whether this metabolite of vitamin D is biologically effective or whether its production simply initiates a catabolic pathway has been a topic of active debate (2, 4, 5, 9). The seco-steroid hormone 1,25(OH)2D exerts its principal biological activities through specific intracellular receptors (Fig. 1), which are nuclear transcription factors of the steroidthyroid receptor gene superfamily (7, 10), a relationship previously postulated on the basis of the biochemical similarities between all these receptor species (1, 11). As now considered likely for many of these ligand-dependent transcription factors, the 1,25(OH)2D receptor (VDR) (12, 13), seems to be predominately a nuclear protein (1), a fact that will be of importance in later discussions of its signal transduction mechanisms. The mechanism of action of the VDR is similar to that of the other steroid hormone receptors (Fig. 2), involving specific interactions of the receptor zinc-finger regions with specific nucleotide sequences (hormone response elements) usually in the 5′-regulatory region of the affected genes (1, 7, 10, 15). Similarly, 1,25(OH)2D regulation of cell function by altering gene transcription and mRNA and protein synthesis is similar to that of the other members of this gene family (1).
The Role of Bacteria in Nitrosamine Formation (1981)

Bacteria have been implicated in the formation of N-nitroso compounds under a wide variety of conditions representing both in vitro and in vivo situations. Mechanisms of participation and/or catalysis include a) decrease of the pH of the system, b) reduction of nitrate to nitrite, c) adsorption of amine onto the cell surface or cytoplasmic membrane, d) actual enzymatic formation. The literature of the field will be reviewed and experimental evidence which tests the above mechanisms will be presented.
THE ANIMAL PHARMACOLOGY OF BUPRENORPHINE, AN ORIPAVINE ANALGESIC AGENT (1977)

1. The general pharmacology of buprenorphine, a potent analgesic agent derived from oripavine, is described. 2. After cute administration of buprenorphine, the spontaneous locomotor activity of mice was increased; rats displayed stereotyped licking and biting movements; behavioural depression was marked in guinea-pigs but mild in rhesus monkeys. The behaviour of cats was unchanged. 3. In general, buprenorphine reduced heart rate but had no significant effect on arterial blood pressure in conscious rats and dogs. 4. In anaesthetized, open-chest cats buprenorphine (0.10 and 1.0 mg/kg, i.v.) caused no major haemodynamic changes. 5. Buprenorphine (0.01-10 mg/kg i.a.) and morphine (0.30-30 mg/kg, i.a.) increased arterial PCO2 values and reduced PO2 values in conscious rats. With doses of buprenorphine greater than 0.10 mg/kg (a) the duration of respiratory depression became less, (b) ceiling effects occurred such that the maximum effects produced were less than those obtained with morphine. 6. Buprenorphine was a potent and long-lasting antagonist of citric acid-induced coughing in guinea-pigs. 7. At a dose level 20 times greater than the ED50 for antinociception (tail pressure), morphine suppressed urine output to a greater extent than the corresponding dose of buprenorphine in rats. 8. Over the range 0.01-1.0 mg/kg (s.c.), buprenorphine slowed the passage of a charcoal meal along the gastrointestinal tract in rats. After doses in excess of 1 mg/kg, the meal travelled increasingly further such that the distances measured at 10 and 30 mg/kg did not differ significantly from control values. In contrast, the morphine dose-response relationship was linear.
Lymph node metastasis could be predicted by evaluation of macrophage infiltration and hsp70 expression in superficial carcinoma of the esophagus (2003)

Macrophages have been reported to play an important role in suppressing tumor growth, and heat shock protein 70 (HSP70) in presenting tumor specific antigens. The objective of the present study was to investigate the relationship between lymph node metastasis and these two molecular biological markers in superficial esophageal carcinoma. Subjects were 37 patients with untreated submucosal esophageal carcinoma who underwent curative surgery. Among these patients, expression of CD68-positive macrophages in the tumor stroma and expression of HSP70 in tumor cells were analyzed. The results demonstrated that expression of CD68-positive macrophages was significantly greater among patients without lymph node metastasis (p<0.0001), and a significant correlation existed between HSP70 expression and CD68 expression (p=0.0125). In superficial esophageal carcinoma, lymph node metastasis is correlated with expression of CD68-positive macrophages in tumor stroma and expression of HSP70 in tumor cells. These two markers may therefore prove useful for therapy planning.
Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers (2004)

A large number of tiny noncoding RNAs have been cloned and named microRNAs (miRs). Recently, we have reported that miR-15a and miR-16a, located at 13q14, are frequently deleted and/or down-regulated in patients with B cell chronic lymphocytic leukemia, a disorder characterized by increased survival. To further investigate the possible involvement of miRs in human cancers on a genome-wide basis, we have mapped 186 miRs and compared their location to the location of previous reported nonrandom genetic alterations. Here, we show that miR genes are frequently located at fragile sites, as well as in minimal regions of loss of heterozygosity, minimal regions of amplification (minimal amplicons), or common breakpoint regions. Overall, 98 of 186 (52.5%) of miR genes are in cancer-associated genomic regions or in fragile sites. Moreover, by Northern blotting, we have shown that several miRs located in deleted regions have low levels of expression in cancer samples. These data provide a catalog of miR genes that may have roles in cancer and argue that the full complement of miRs in a genome may be extensively involved in cancers.
Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease (2000)

Profound overexpression of MMP-1 and MMP-3 mRNA transcripts suggests an important role for these enzymes in the process of tissue remodelling and destruction in inflammatory bowel disease.
RNA Interference-Based Gene Silencing as an Efficient Tool for Functional Genomics in Hexaploid Bread Wheat (2006)

Insertional mutagenesis and gene silencing are efficient tools for the determination of gene function. In contrast to gain- or loss-of-function approaches, RNA interference (RNAi)-induced gene silencing can possibly silence multigene families and homoeologous genes in polyploids. This is of great importance for functional studies in hexaploid wheat (Triticum aestivum), where most of the genes are present in at least three homoeologous copies and conventional insertional mutagenesis is not effective. We have introduced into bread wheat double-stranded RNA-expressing constructs containing fragments of genes encoding Phytoene Desaturase (PDS) or the signal transducer of ethylene, Ethylene Insensitive 2 (EIN2). Transformed plants showed phenotypic changes that were stably inherited over at least two generations. These changes were very similar to mutant phenotypes of the two genes in diploid model plants. Quantitative real-time polymerase chain reaction revealed a good correlation between decreasing mRNA levels and increasingly severe phenotypes. RNAi silencing had the same quantitative effect on all three homoeologous genes. The most severe phenotypes were observed in homozygous plants that showed the strongest mRNA reduction and, interestingly, produced around 2-fold the amount of small RNAs compared to heterozygous plants. This suggests that the effect of RNAi in hexaploid wheat is gene-dosage dependent. Wheat seedlings with low mRNA levels for EIN2 were ethylene insensitive. Thus, EIN2 is a positive regulator of the ethylene-signaling pathway in wheat, very similar to its homologs in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa). Our data show that RNAi results in stably inherited phenotypes and therefore represents an efficient tool for functional genomic studies in polyploid wheat.
Cytokines in Alcoholic and Nonalcoholic Steatohepatitis (2000)

Cytokines are pleiotropic regulatory peptides that can be produced by virtually every nucleated cell in the body, including most types of liver cells.1,2 The cytokine family consists of several subfamilies: the interleukins, the tumor necrosis factor (TNF) family, interleukin-6 and related cytokines, interferons, chemokines such as interleukin-8, transforming growth factor β, colony-stimulating factors, and others.In most tissues, including the liver, constitutive production of cytokines is absent or minimal. However, as physiologic and pathologic stimuli activate cells, the production of these autocrine, paracrine, and endocrine effector molecules increases, and they, in turn, orchestrate the tissue's response to the stimulus. . . .
A Comparison of Accuracy Using a GPS and a Low-Cost DGPS (2006)

After the cancellation of selective availability in May 2000, the accuracy of plain uncorrected global positioning systems (GPSs) is significantly increased. Currently, the main cause of error in plain GPS receivers is imperfect compensation of the ionospheric error. Tests performed in New Zealand show that even a simple code range differential GPS (DGPS) provides significant improvement in accuracy over a plain GPS and can be implemented using low-cost off-the-shelf equipment. A simple statistical model of positioning error estimation is developed and applied on data obtained by measurements in order to verify the findings. The method, which needs only position information without satellite constellation, provides sufficient accuracy when simultaneously gathered plain GPS and DGPS data are compared.
Cloning and molecular analysis of the poly(3‐hydroxyalkanoic acid) gene locus of Pseudomonas aeruginosa PAO1 (1992)

From genomic libraries, the polyhydroxyalkanoate gene locus of Pseudomonas aeruginosa PAO1 was cloned and characterised at the molecular level. Two genes coding for polyhydroxyalkanoate synthases, phaC1Pa and phaC2Pa, a polyhydroxyalkanoate depolymerase gene, phaDPa, and four adjacent open reading frames (ORF1, ORF2, ORF3 and ORF4) were identified from the nucleotide sequence. Two transcriptional start sites, which were preceded by sequences resembling the Escherichia coli consensus sequences for sigma 54 and sigma 70 promoters, were identified experimentally upstream of phaC1Pa, which was shown by Northern blot analysis to constitute an operon together with phaDPa. A third putative promoter resembling the E. coli consensus sequence for sigma 70-dependent promoters was proposed upstream of phaC2Pa, which is in a bicistronic operon with ORF3. Investigations of rpoN-negative mutants of related strains revealed that polyhydroxyalkanoate accumulation from gluconate required an intact rpoN locus in P. aeruginosa. Complementation experiments revealed multiple evidence that either polyhydroxyalkanoate synthase is involved in polyhydroylkanoate accumulation from gluconate as well as from octanoate. The P. aeruginosa PAO1 polyhydroxyalkanoate gene locus was expressed in the polyhydroxyalkanoate-negative mutant Alcaligenes eutrophus PHB-4 and in the poly(3-hydroxybutyrate)-accumulating strain P. oleovorans DSM1045. It conferred on the latter the ability to synthesize and accumulate polyhydroxyalkanoates consisting of medium-chain-length 3-hydroxyalkanoic acids from unrelated substrates in addition to poly(3-hydroxybutyrate). The sequence of the putative translational product of ORF1 was similar to those of the leukotoxin repressor of Pasteurella haemolytica and to the ORF9 product of Azotobacter vinelandii, and that of ORF4 was similar to the algP product of P. aeruginosa and to eukaryotic histone H1 proteins. The proteins of ORF2 and ORF3 appear to be previously unidentified.
In Vivo Instruction of Suppressor Commitment in Naive T Cells (2004)

The induction of antigen-specific tolerance in the mature immune system of the intact organism has met with limited success. Therefore, nonspecific immunosuppression has been the treatment of choice to prevent unwanted immunity. Here, it is shown that prolonged subcutaneous infusion of low doses of peptide by means of osmotic pumps transforms mature T cells into CD4+25+ suppressor cells that can persist for long periods of time in the absence of antigen and confer specific immunologic tolerance upon challenge with antigen. The described procedure resembles approaches of tolerance induction used decades ago, induces tolerance in the absence of immunity, and holds the promise to become an effective means of inducing antigen-specific tolerance prospectively, whereas its power to suppress already ongoing immune responses remains to be determined.
Functional Expression of Human Dihydroorotate Dehydrogenase (DHODH) in pyr4 Mutants of Ustilago maydis Allows Target Validation of DHODH Inhibitors In Vivo (2007)

Dihydroorotate dehydrogenase (DHODH; EC 1.3.99.11) is a central enzyme of pyrimidine biosynthesis and catalyzes the oxidation of dihydroorotate to orotate. DHODH is an important target for antiparasitic and cytostatic drugs since rapid cell proliferation often depends on the de novo synthesis of pyrimidine nucleotides. We have cloned the pyr4 gene encoding mitochondrial DHODH from the basidiomycetous plant pathogen Ustilago maydis. We were able to show that pyr4 contains a functional mitochondrial targeting signal. The deletion of pyr4 resulted in uracil auxotrophy, enhanced sensitivity to UV irradiation, and a loss of pathogenicity on corn plants. The biochemical characterization of purified U. maydis DHODH overproduced in Escherichia coli revealed that the U. maydis enzyme uses quinone electron acceptor Q6 and is resistant to several commonly used DHODH inhibitors. Here we show that the expression of the human DHODH gene fused to the U. maydis mitochondrial targeting signal is able to complement the auxotrophic phenotype of pyr4 mutants. While U. maydis wild-type cells were resistant to the DHODH inhibitor brequinar, strains expressing the human DHODH gene became sensitive to this cytostatic drug. Such engineered U. maydis strains can be used in sensitive in vivo assays for the development of novel drugs specifically targeted at either human or fungal DHODH.