gebhart/patrepeval huggingface dataset:
Deletion mapping a eukaryotic promoter. (1981)

The phenotypes of 24 mutants that successively delete DNA sequences adjacent to the 5' end of the Saccharomyces cerevisiae (yeast) his3 structural gene are described. Deletions retaining greater than 155 base pairs before the mRNA coding sequences are phenotypically indistinguishable from the wild-type his3 allele. Deletions having end points between 113 and 65 base pairs before the transcription initiation site express his3 at reduced levels. Mutations retaining less than 45 base pairs are indistinguishable from null alleles of the his3 locus. These results indicate (i) that a sequence(s) located 113--155 base pairs upstream from the transcribed region is necessary for wild-type expression and (ii) that the T-A-T-A box (a sequence in front of most eukaryotic genes) is not sufficient for wild-type promoter function. Thus, the yeast his3 promoter region appears large when compared with prokaryotic promoters, suggesting that it may be more complex than a simple site of interaction between RNA polymerase and DNA.
Discovery and Validation of a Series of Aryl Sulfonamides as Selective Inhibitors of Tissue-Nonspecific Alkaline Phosphatase (TNAP) (2009)

We report the characterization and optimization of drug-like small molecule inhibitors of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme critical for the regulation of extracellular matrix calcification during bone formation and growth. High-throughput screening (HTS) of a small molecule library led to the identification of arylsulfonamides as potent and selective inhibitors of TNAP. Critical structural requirements for activity were determined, and the compounds were subsequently profiled for in vitro activity and bioavailability parameters including metabolic stability and permeability. The plasma levels following subcutaneous administration of a member of the lead series in rat was determined, demonstrating the potential of these TNAP inhibitors as systemically active therapeutic agents to target various diseases involving soft tissue calcification. A representative member of the series was also characterized in mechanistic and kinetic studies.
Group Analysis in Practice: Narrative Approaches (2015)

Working in groups is increasingly regarded as fruitful for the process of analyzing qualitative data. It has been reported to build research skills, make the analytic process visible, reduce inequalities and social distance particularly between researchers and participants, and broaden and intensify engagement with the material. This article contributes to the burgeoning literature on group qualitative data analysis by presenting a worked example of a group data analysis of a short extract from an interview on serial migration from the Caribbean to the UK. It describes the group's working practices and the different analytic resources drawn upon to conduct a narrative analysis. We demonstrate the ways in which an initial line-by-line analysis followed by analysis of larger extracts generated insights that would have been less available to individual researchers. Additionally, we discuss the positioning of group members in relation to the data and reflect on the porous boundary between primary and secondary analysis of qualitative data. URN: http://nbn-resolving.de/urn:nbn:de:0114-fqs160294
Radiofrequency-induced hyperthermia: computer simulation of specific absorption rate distributions using realistic anatomical models (1983)

A description is given of a computer simulation technique which predicts the specific absorption rate (SAR) distribution within the human body resulting from the application of radiofrequency electromagnetic energy. The method uses an extension to the principle of over-relaxation of electric potentials and the basis of the simulation is a realistic three-dimensional model derived from both dielectric and anatomical data. Two of the principal means of applying radiofrequency hyperthermia, namely the use of capacitive electrodes and inductive coils, have been provided for. The accuracy of the simulation has been favourably tested using an agar split-phantom and an infrared thermograph camera. The simulations can be used to assist the design and clinical use of radiofrequency applicators, and examples are given of the application of both an inductive coil and switched capacitive electrodes to heat the thorax.
Behavior of transaldolase (EC 2.2.1.2) and transketolase (EC 2.2.1.1) Activities in normal, neoplastic, differentiating, and regenerating liver. (1976)

The objective of this investigation was to throw light on the biological behavior and metabolic regulation of hepatic enzymes of the nonoxidative branch of the pentose phosphate pathway. The activities of transaldolase (EC 2.2.1.2) and trasketolase (EC 2.2.1.1) Were compared in biological conditions that involve modulation of gene expression such as in starvation, in differentiation, after partial hepatectomy, and in a spectrum of hepatomas of different growth rates. The enzyme activities were determined under optimal kinetic conditions by spectrophotometric methods in the 100,000 X g supernatant fluids prepared from tissue homogenates. The kinetic properties of transaldolase and transketolase were similar in normal liver and in rapidly growing hepatoma 3924A. For transaldolase, apparent Km values of 0.13 mM (normal liver) and 0.17 mM (hepatoma) were observed for erythrose 4-phosphate and of 0.30 to 0.35 mM for fructose 6-phosphate. The pH optima in liver and hepatoma were at approximately 6.9 to 7.2. For the transketolase substrates, ribose 5-phosphate and xylulose 5-phosphate, the apparent Km values were 0.3 and 0.5 mM, respectively, in both liver and hepatoma. A broad pH optimum around 7.6 was observed in both tissues. In organ distribution studies, enzyme activities were measured in liver, intestinal mucosa, thymus, kidney, spleen, brain, adipose tissue, lung, heart, and skeletal muscle. Taking the specific activity of liver as 100%, transaldolase activity was the highest in intestinal mucosa (316%) and in thymus (219%); it was the lowest in heart (53%) and in skeletal muscle (21%). Transketolase activity was highest in kidney (155%) and lowest in heart (26%) and skeletal muscle (23%). Starvation decreased transaldolase and transketolase activities in 6 days to 69 and 74%, respectively, of those of the liver of the normal, fed rat. This was in the same range as the decrease in the protein concentration (66%y. In the liver tumors, transaldolase activity was increased 1.5- to 3.4-fold over the activities observed in normal control rat liver. Transketolase activity showed no relationship to tumor proliferation rate. In the regenerating liver at 24 hr after partial hepatectomy, the activity of both pentose phosphate pathway enzymes was in the same range as that of the sham-operated controls. In differentiation at the postnatal age of 5, 12, 23, and 32 days, hepatic transaldolase activities were 33, 44, 55, and 72%, respectively, of the activities observed in the 60-day-old, adult male rat. During the same period, transketolase activ-ties were 18, 21, 26, and 55% of the activities observed in liver of adult rat. The demonstration of increased transaldolase activity in hepatomas, irrespective of the degree of tumor malignancy, differentiation, or growth rate, suggests that the reprogramming of gene expression in malignant transformation is linked with an increase in the expression of this pentose phosphate pathway enzyme...
Sensor networks: Evolution, opportunities, and challenges (2003)

Wireless microsensor networks have been identified as one of the most important technologies for the 21st century. This paper traces the history of research in sensor networks over the past three decades, including two important programs of the Defense Advanced Research Projects Agency (DARPA) spanning this period: the Distributed Sensor Networks (DSN) and the Sensor Information Technology (SensIT) programs. Technology trends that impact the development of sensor networks are reviewed, and new applications such as infrastructure security, habitat monitoring, and traffic control are presented. Technical challenges in sensor network development include network discovery, control and routing, collaborative signal and information processing, tasking and querying, and security. The paper concludes by presenting some recent research results in sensor network algorithms, including localized algorithms and directed diffusion, distributed tracking in wireless ad hoc networks, and distributed classification using local agents.
Cooperation of c-raf-1 and c-myc protooncogenes in the neoplastic transformation of simian virus 40 large tumor antigen-immortalized human bronchial epithelial cells. (1989)

Overexpression of c-raf-1 and the myc family of protooncogenes is primarily associated with small cell carcinoma, which accounts for approximately 25% of human lung cancer. To determine the functional significance of the c-raf-1 and/or c-myc gene expression in lung carcinogenesis and to delineate the relationship between protooncogene expression and tumor phenotype, we introduced both protooncogenes, alone or in combination, into human bronchial epithelial cells. Two retroviral recombinants, pZip-raf and pZip-myc, containing the complete coding sequences of the human c-raf-1 and murine c-myc genes, respectively, were constructed and transfected into simian virus 40 large tumor antigen-immortalized bronchial epithelial cells (BEAS-2B); this was followed by selection for G418 resistance. BEAS-2B cells expressing both the transfected c-raf-1 and c-myc sequences formed large cell carcinomas in athymic nude mice with a latency of 4-21 weeks, whereas either pZip-raf- or pZip-myc-transfected cells were nontumorigenic after 12 months. Cell lines established from tumors (designated RMT) revealed the presence of the cotransfected c-raf-1 and c-myc sequences and expressed morphological, chromosomal, and isoenzyme markers, which identified BEAS-2B cells as the progenitor line of the tumors. A significant increase in the mRNA levels of neuron-specific enolase was detected in BEAS-2B cells containing both the c-raf-1 and c-myc genes and derived tumor cell lines. The data demonstrate that the concomitant expression of the c-raf and c-myc protooncogenes causes neoplastic transformation of human bronchial epithelial cells resulting in large cell carcinomas with certain neuroendocrine markers. The presented model system should be useful in studies of molecular events involved in multistage lung carcinogenesis.
Protein-Specific Helper T-Lymphocyte Formation Initiated by Dendritic Cells (1985)

Antibody responses to hapten-polypeptide conjugates require peptide-specific helper T cells. The latter can be primed in tissue culture by providing small numbers of dendritic cells. Primed, irradiated helper T cells then induce B-cell growth and differentiation in the apparent absence of dendritic cells. Both stages of the antibody response--the induction of helper T lymphoblasts by dendritic cells and the delivery of help from T to B cell--occur in discrete cell aggregates that can be isolated by velocity sedimentation. If helper T blasts revert to smaller "memory" lymphocytes, dendritic cells again are needed to initiate the antibody response.
Identifying and analyzing judgment opinions (2006)

In this paper, we introduce a methodology for analyzing judgment opinions. We define a judgment opinion as consisting of a valence, a holder, and a topic. We decompose the task of opinion analysis into four parts: 1) recognizing the opinion; 2) identifying the valence; 3) identifying the holder; and 4) identifying the topic. In this paper, we address the first three parts and evaluate our methodology using both intrinsic and extrinsic measures.
Effect of short-chain fatty acids on the secretory response of the ovine exocrine pancreas (1983)

The secretory response of the exocrine pancreas to short-chain fatty acids has been studied in anesthetized sheep and in isolated lobules. Butyrate, propionate, and acetate stimulated pancreatic juice flow and protein and amylase output in the anesthetized sheep. The secretory response to butyrate was significantly greater than that of propionate or acetate. Rapid intravenous injection of butyrate (625 mumol/kg) caused a 13-fold rise in the juice flow, 26-fold in protein output, and 37-fold in amylase output above the basal levels within 5 min and declined to basal levels over a period of 30 min. Responses to butyrate (625 mumol/kg) were comparable with those obtained with 2 U/kg pancreozymin (Boots). Detectable responses were obtained with 15 mu/kg butyrate, 125 mumol/kg propionate, and 312.5 mumol/kg acetate. The secretory response to butyrate (625 mumol/kg) was not affected by pretreatment with atropine and hexamethonium. In the isolated lobule preparation, amylase release increased in response to butyrate in a concentration-dependent manner, reaching a maximal level at 1 mM and declining at 100 mM. It is concluded that short-chain fatty acids act directly on pancreatic acinar cells to stimulate secretion. The physiological implications of these findings are considered.
Protein Tubule Immobilization on Self-Assembled Monolayers on Au Substrates (2001)

Avidin-coated peptide tubules, protein tubules, were anchored onto biotin-incorporated self-assembled monolayers (SAMs) on Au substrates and assembled as bridges between the SAMs. The patterned biotin-SAM/Au substrates were placed in a citric acid solution (pH 6) with the protein tubules. After 12 h, the avidin tubules were immobilized on the biotin-SAMs and some of the tubules bridged the patterned biotin-SAMs. No avidin tubules were found to attach onto the glass region between the biotin-SAM/Au substrates. This result shows that the protein tubules have potential to serve as connecting wires for microelectronics.
Parthenogenic Activation of Pig Oocytes by Protein Kinase Inhibition1 (1995)

Previous studies have shown that protein kinase stimulators can induce the release of the metaphase II arrest in mouse ova. The present report is about the role of protein kinase in parthenogenic activation of pig oocytes, which was studied using a broad-spectrum protein kinase inhibitor. Metaphase II oocytes were obtained via in vitro maturation. Two sources of H7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine, HCl] were tested--Sigma (H7s) and Calbiochem (H7c). Both were found to be equally effective in promoting release of the metaphase II block. Activation, release of the metaphase II arrest, and progression to the first interphase could be induced at the highest percentage with an exposure to 2.0 mM H7s for 80 min (68.1%). In another experiment, H7c resulted in 69.5% activation, while iso-H7 [1-(5-isoquinolinesulfonyl)-3-methylpiperazine, HCl] at a similar concentration and exposure duration resulted in 25.7% activation. H7s and H7c were more effective than iso-H7 in inducing the appearance of a 22-kDa protein that is associated with normal fertilization in the pig. In contrast, although pronuclei could form and the protein profiles were indicative of activation, cortical granule exocytosis did not occur, and oocytes failed to develop to the blastocyst stage after H7 treatment. In contrast to the H7-treated oocytes, electrostimulation resulted in pronuclear formation, the appearance of the 22-kDa protein, release of cortical granules, and development to the blastocyst stage. These data demonstrate that broad-spectrum inhibitors of protein kinase are unable to induce all the events associated with normal fertilization.
High-speed high-performance liquid chromatography of peptides and proteins (1995)

Over the last thirty years the name HPLC has been synonymous with high-speed liquid chromatography and during the last ten years we have experienced a dramatic increase in the speed of analysis particularly as far as the separation of biological macromolecules, such as proteins, is concerned. With a solid grounding in the chromatographic theories, column technology has been mainly responsible for the advances in this field. Recent development shows that columns packed with micropellicular or gigaporous stationary phases of the bidisperse or the bimodal type facilitate rapid mass transfer between the mobile and stationary phases and thus can deliver high resolution separations in a very short time. This suggest that HPLC has the potential to be the prime analytical technique for on-line monitoring of biotechnological processes in real time. Further enhancement of the speed of separation comes from the use of elevated temperatures. The role of temperature in HPLC has largely been ignored and most commercial instruments are not equipped with appropriate temperature control. Results presented here strongly suggest, however, that elevated column temperature may find increasing use in the HPLC of large molecules. In such analytical applications temperature programming may also play a major role provided columns with low heat capacity, such as packed fused-silica capillaries, gain wider employment in HPLC.
Zfp423 Is Required for Normal Cerebellar Development (2006)

Zinc finger protein 423 (also known as Ebf-associated zinc finger protein, Ebfaz) binds to and negatively regulates Ebf1, a basic helix-loop-helix transcription factor required for B-cell lineage commitment and olfactory epithelium development. Zfp423 also binds to Smad1/Smad4 in response to Bmp2 signaling. Zfp423 contains 30 Krüppel-like zinc fingers that are organized into discrete clusters; some zinc fingers are used to bind DNA, while others mediate Zfp423's interaction with other signaling proteins such as Ebf1 and Smad1/Smad4. Previously, we showed that Zfp423 is an oncogene whose upregulation following retroviral integration in murine B cells leads to an arrest in B-cell differentiation and the subsequent development of B-cell lymphomas. To study the biological functions of Zfp423 in vivo, we used recombineering and gene targeting to generate mice that carry conditional as well as null alleles of Zfp423. Homozygous Zfp423 null mice are runted and ataxic, the cerebellum is underdeveloped, and the vermis is severely reduced. In the remaining cerebellar structures, the Purkinje cells are poorly developed and mislocalized. In mice carrying a hypomorphic Zfp423 gene trap allele, lacZ expression in the cerebellum correlates with the Purkinje cell layer, suggesting that these phenotypes are a result of a Purkinje cell-intrinsic defect.
Age-Dependent Impairment of Endothelial Progenitor Cells Is Corrected by Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1 (2007)

Aging is associated with an increased risk for atherosclerosis. A possible cause is low numbers and dysfunction of endothelial progenitor cells (EPC) which insufficiently repair damaged vascular walls. We hypothesized that decreased levels of insulin-like growth factor-1 (IGF-1) during age contribute to dysfunctional EPC. We measured the effect of growth hormone (GH), which increases endogenous IGF-1 levels, on EPC in mice and human subjects. We compared EPC number and function in healthy middle-aged male volunteers (57.4+/-1.4 years) before and after a 10 day treatment with recombinant GH (0.4 mg/d) with that of younger and elderly male subjects (27.5+/-0.9 and 74.1+/-0.9 years). Middle-aged and elderly subjects had lower circulating CD133(+)/VEGFR-2(+) EPC with impaired function and increased senescence. GH treatment in middle-aged subjects elevated IGF-1 levels (126.0+/-7.2 ng/mL versus 241.1+/-13.8 ng/mL; P<0.0001), increased circulating EPC with improved colony forming and migratory capacity, enhanced incorporation into tube-like structures, and augmented endothelial nitric oxide synthase expression in EPC comparable to that of the younger group. EPC senescence was attenuated, whereas telomerase activity was increased after GH treatment. Treatment of aged mice with GH (7 days) or IGF-1 increased IGF-1 and EPC levels and improved EPC function, whereas a two day GH treatment did not alter IGF-1 or EPC levels. Ex vivo treatment of EPC from elderly individuals with IGF-1 improved function and attenuated cellular senescence. IGF-1 stimulated EPC differentiation, migratory capacity and the ability to incorporate into forming vascular networks in vitro via the IGF-1 receptor. IGF-1 increased telomerase activity, endothelial nitric oxide synthase expression, phosphorylation and activity in EPC in a phosphoinositide-3-kinase/Akt dependent manner. Small interference RNA-mediated knockdown of endothelial nitric oxide synthase in EPC abolished the IGF-1 effects. Growth hormone-mediated increase in IGF-1 reverses age-related EPC dysfunction and may be a novel therapeutic strategy against vascular disorders with impairment of EPC.
Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts (2004)

The role of TGF-beta/bone morphogenetic protein signaling in the chondrogenic differentiation of human synovial fibroblasts (SFs) was examined with the adenovirus vector-mediated gene transduction system. Expression of constitutively active activin receptor-like kinase 3 (ALK3CA) induced chondrocyte-specific gene expression in SFs cultured in pellets or in SF pellets transplanted into nude mice, in which both the Smad and p38 pathways are essential. To analyze downstream cascades of ALK3 signaling, we utilized adenovirus vectors carrying either Smad1 to stimulate Smad pathways or constitutively active MKK6 (MKK6CA) to activate p38 pathways. Smad1 expression had a synergistic effect on ALK3CA, while activation of p38 MAP kinase pathways alone by transduction of MKK6CA accelerated terminal chondrocytic differentiation, leading to type X collagen expression and enhanced mineralization. Overexpression of Smad1 prevented MKK6CA-induced type X collagen expression and maintained type II collagen expression. In a mouse model of osteoarthritis, activated p38 expression as well as type X collagen staining was detected in osteochondrophytes and marginal synovial cells. These results suggest that SFs can be differentiated into chondrocytes via ALK3 activation and that stimulating Smad pathways and controlling p38 activation at the proper level can be a good therapeutic strategy for maintaining the healthy joint homeostasis and treating degenerative joint disorders.
Mechanisms of age‐related macular degeneration and therapeutic opportunities (2013)

As the age of the population increases in many nations, age-related degenerative diseases pose significant socioeconomic challenges. One of the key degenerative diseases that compromise quality of life is age-related macular degeneration (AMD). AMD is a multi-faceted condition that affects the central retina, which ultimately leads to blindness in millions of people worldwide. The pathophysiology and risk factors for AMD are complex, and the symptoms manifest in multiple related but distinct forms. The ability to develop effective treatments for AMD will depend on a thorough understanding of the underlying pathophysiology, risk factors, and driver molecular pathways, as well as the ability to develop useful animal models. This review provides an overview of the aforementioned aspects in AMD.