gebhart/patrepeval huggingface dataset:
Transdifferentiation versus stem cell hypothesis for the regeneration of islet beta-cells in the pancreas (1998)

The pancreas is composed of at least three types of differentiated tissue: the hormone-containing cells in islets (4 different cell types), the exocrine zymogen-containing acini, and the centroacinar cells, ductules and ducts (ductal tree). All of these cells appear to have a common origin during embryogenesis in the form of duct-like protodifferentiated cells. Later in life, the acinar and ductal cells retain a significant proliferative capacity that can ensure cell renewal and growth, whereas the islet cells become mitotically inactive. Interestingly, new islet cells, including the insulin-producing beta-cells, can regenerate after tissue injury by a process called neogenesis. The neogenetic process involves differentiation of duct-like (exocrine) epithelial cells to hormone-expressing cells. In this paper, we review the question whether islet β-cell regeneration or neogenesis in the pancreas depends on “embryonic-like” stem cells or on transdifferentiation of “fully differentiated” cells. This issue is important to find the right model for in vitro research aiming at controlling the process of beta-cell neogenesis. The latter could lead to applications in the treatment of diabetes where functional beta-cells are deficient. We conclude from the available evidence that there is as yet no evidence for the existence of “dormant” stem cells in the adult pancreas. There is some evidence, however, that differentiated exocrine acinar and/or duct cells retain the capacity to transdifferentiate into insulin-expressing beta-cells. Miscrosc. Res. Tech. 43:332–336, 1998. © 1998 Wiley-Liss, Inc.
Construction of Environmental DNA Libraries in Escherichia coli and Screening for the Presence of Genes Conferring Utilization of 4-Hydroxybutyrate (1999)

Environmental DNA libraries from three different soil samples were constructed. The average insert size was 5 to 8 kb and the percentage of plasmids with inserts was approximately 80%. The recombinant Escherichia coli strains (approximately 930,000) were screened for 4-hydroxybutyrate utilization. Thirty-six positive E. coli clones were obtained during the initial screen, and five of them contained a recombinant plasmid (pAH1 to pAH5) which conferred a stable 4-hydroxybutyrate-positive phenotype. These E. coli clones were studied further. All five were able to grow with 4-hydroxybutyrate as sole carbon and energy source and exhibited 4-hydroxybutyrate dehydrogenase activity in crude extracts. Sequencing of pAH5 revealed a gene homologous to the gbd gene of Ralstonia eutropha, which encodes a 4-hydroxybutyrate dehydrogenase. Two other genes (orf1 and orf6) conferring utilization of 4-hydroxybutyrate were identified during subcloning and sequencing of the inserts of pAH1 and pAH3. The deduced orf1 gene product showed similarities to members of the DedA family of proteins. The sequence of the deduced orf6 gene product harbors the fingerprint pattern of enoyl-coenzyme A hydratases/isomerases. The other sequenced inserts of the plasmids recovered from the positive clones revealed no significant similarity to any other gene or gene product whose sequence is available in the National Center for Biotechnology Information databases.
Identification of a cancer stem cell in human brain tumors. (2003)

Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and self-renewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133+ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.
Limit Pricing and Entry under Incomplete Information: An Equilibrium Analysis (1982)

Limit pricing involves charging prices below the monopoly price to make new entry appear unattractive.If the entrant is a rational decision maker with complete information, pre-entry prices will not influence its entry decision, so the established firm has no incentive to practice limit pricing.However, if the established firm has private, payoff relevant information (e.g., about costs), then prices can signal that information, so limit pricing can arise in equilibrium.The probability that entry actually occurs in such an equilibrium, however, can be lower, the same, or even higher than in a regime of complete information (where no limit pricing would occur).'Much of the work reported here first appeared in [11].This work has been presented at a large number of conferences, meetings, and seminars, and we would like to thank our audiences at each of these events for their comments.We are particularly indebted to Eric Maskin, Roger Myerson, Steve Salop, Robert Wilson, and two referees for their helpful suggestions, to David Besanko for his excellent research assistance,
Antiparasitic Drug Nitazoxanide Inhibits the Pyruvate Oxidoreductases of Helicobacter pylori , Selected Anaerobic Bacteria and Parasites, and Campylobacter jejuni (2006)

Nitazoxanide (NTZ) exhibits broad-spectrum activity against anaerobic bacteria and parasites and the ulcer-causing pathogen Helicobacter pylori. Here we show that NTZ is a noncompetitive inhibitor (K(i), 2 to 10 microM) of the pyruvate:ferredoxin/flavodoxin oxidoreductases (PFORs) of Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis, Clostridium difficile, Clostridium perfringens, H. pylori, and Campylobacter jejuni and is weakly active against the pyruvate dehydrogenase of Escherichia coli. To further mechanistic studies, the PFOR operon of H. pylori was cloned and overexpressed in E. coli, and the multisubunit complex was purified by ion-exchange chromatography. Pyruvate-dependent PFOR activity with NTZ, as measured by a decrease in absorbance at 418 nm (spectral shift from 418 to 351 nm), unlike the reduction of viologen dyes, did not result in the accumulation of products (acetyl coenzyme A and CO(2)) and pyruvate was not consumed in the reaction. NTZ did not displace the thiamine pyrophosphate (TPP) cofactor of PFOR, and the 351-nm absorbing form of NTZ was inactive. Optical scans and (1)H nuclear magnetic resonance analyses determined that the spectral shift (A(418) to A(351)) of NTZ was due to protonation of the anion (NTZ(-)) of the 2-amino group of the thiazole ring which could be generated with the pure compound under acidic solutions (pK(a) = 6.18). We propose that NTZ(-) intercepts PFOR at an early step in the formation of the lactyl-TPP transition intermediate, resulting in the reversal of pyruvate binding prior to decarboxylation and in coordination with proton transfer to NTZ. Thus, NTZ might be the first example of an antimicrobial that targets the "activated cofactor" of an enzymatic reaction rather than its substrate or catalytic sites, a novel mechanism that may escape mutation-based drug resistance.
Delineation of the Exact Transcription Termination Signal for Type 3 Polymerase III (2017)

Type 3 Pol III promoters such as U6 are widely used for expression of small RNAs, including short hairpin RNA for RNAi applications and guide RNA in CRISPR genome-editing platforms. RNA polymerase III uses a T-stretch as termination signal, but the exact properties have not been thoroughly investigated. Here, we systematically measured the in vivo termination efficiency and the actual site of termination for different T-stretch signals in three commonly used human Pol III promoters (U6, 7SK, and H1). Both the termination efficiency and the actual termination site depend on the T-stretch signal. The T4 signal acts as minimal terminator, but full termination efficiency is reached only with a T-stretch of ≥6. The termination site within the T-stretch is quite heterogeneous, and consequently small RNAs have a variable U-tail of 1-6 nucleotides. We further report that such variable U-tails can have a significant negative effect on the functionality of the crRNA effector of the CRISPR-AsCpf1 system. We next improved these crRNAs by insertion of the HDV ribozyme to avoid U-tails. This study provides detailed design guidelines for small RNA expression cassettes based on Pol III.
Activation of an intron enhancer within the keratin 18 gene by expression of c-fos and c-jun in undifferentiated F9 embryonal carcinoma cells. (1990)

The mouse forms of human keratins 18 and 8 (K18 and K8) are the first members of the large intermediate filament gene family to be expressed during embryogenesis. To identify potential regulatory elements of the human K18 gene, various recombinant constructions were expressed in cultured cells. An enhancer element was found in the first intron that functions on both the K18 and thymidine kinase promoters in differentiated cells. In F9 embryonal carcinoma cells, the level of expression was low in the presence or absence of the first intron. Cotransfection of F9 cells with K18 constructs that include the first intron and increasing amounts of an expression vector of c-jun results in a modest increase in the reporter gene expression. Cotransfection of the same construct with increasing amount of the mouse c-fos gene results in activation of the reporter gene by as much as 15-fold, with a near linear response to the amount of c-fos gene added. Site-specific mutagenesis of a putative AP-1 site within the intron abolishes trans-activation by c-fos in F9 cells. Furthermore, induction of c-fos in a derivative of F9 cells results in increased expression of the endogenous mouse form of K18. Cotransfection with c-jun or c-fos expression vectors had little effect on the expression of the K18 reporter construct in a parietal endodermal cell line already expressing the endogenous mouse gene. These results identify an enhancer within the first intron of K18 that may interact directly with c-jun and c-fos via a conserved AP-1-binding site. K18 expression in undifferentiated F9 cells may be limited by the low levels of c-jun and c-fos.
Osteocalcin binds tightly to the γ-glutamylcarboxylase at a site distinct from that of the other known vitamin K-dependent proteins (1999)

Vitamin K-dependent proteins contain a propeptide that is required for recognition by the enzyme gamma-glutamylcarboxylase. Substrates used in vitro for carboxylation studies lacking a prosequence are characterized by Km values in the millimolar range, whereas the Km for peptides containing a prosequence is three or four orders of magnitude smaller. Here we report that descarboxy-osteocalcin is an exception in this respect. With descarboxy-osteocalcin in purified propeptide-free recombinant carboxylase, the Km was 1.8 microM. Furthermore, osteocalcin was an inhibitor of descarboxy-osteocalcin carboxylation with a Ki of 76 microM. In contrast with the other vitamin K-dependent proteins, free propeptides do not inhibit descarboxy-osteocalcin carboxylation. Moreover, propeptide-containing substrates were inhibited neither by osteocalcin nor by its propeptide. From our studies we conclude that descarboxy-osteocalcin must have an internal recognition sequence that binds to gamma-glutamylcarboxylase at a site different from the propeptide-recognition site.
Cooperation of sperm in two dimensions: Synchronization, attraction, and aggregation through hydrodynamic interactions (2008)

Sperm swimming at low Reynolds number have strong hydrodynamic interactions when their concentration is high in vivo or near substrates in vitro. The beating tails not only propel the sperm through a fluid, but also create flow fields through which sperm interact with each other. We study the hydrodynamic interaction and cooperation of sperm embedded in a two-dimensional fluid by using a particle-based mesoscopic simulation method, multiparticle collision dynamics. We analyze the sperm behavior by investigating the relationship between the beating-phase difference and the relative sperm position, as well as the energy consumption. Two effects of hydrodynamic interaction are found, synchronization and attraction. With these hydrodynamic effects, a multisperm system shows swarm behavior with a power-law dependence of the average cluster size on the width of the distribution of beating frequencies.
Calcium ions and oxidative cell injury (1992)

Exposure of mammalian cells to oxidative stress induced by oxidation-reduction-active quinones and other prooxidants results in depletion of intracellular glutathione, followed by modification of protein thiols and loss of cell viability. Protein thiol modification during oxidative stress is normally associated with impairment of various cell functions, including inhibition of agonist-stimulated phosphoinositide metabolism, disruption of intracellular Ca2+ homeostasis, and perturbation of normal cytoskeletal organization. The latter effect appears to be responsible for formation of the numerous plasma membrane blebs typically seen in cells exposed to cytotoxic concentrations of prooxidants. Following disruption of thiol homeostasis in prooxidant-treated cells, there is impairment of Ca2+ transport and subsequent perturbation of intracellular Ca2+ homeostasis, resulting in a sustained increase in cytosolic Ca2+ concentration. This increase in Ca2+ can cause activation of various Ca(2+)-dependent degradative enzymes (e.g., phospholipases, proteases, endonucleases), which may contribute to cell death. In contrast to the cytotoxic effects of excessive oxidative damage, low levels of oxidative stress can lead to activation of enzymes involved in cell signaling. In particular, the activity of protein kinase C is markedly increased by oxidation-reduction-cycling quinones through a thiol/disulfide exchange mechanism, which may represent a mechanism by which prooxidants can modulate cell growth and differentiation.
The type 1 human immunodeficiency virus Tat binding protein is a transcriptional activator belonging to an additional family of evolutionarily conserved genes. (1993)

The type 1 human immunodeficiency virus Tat protein is a powerful transcriptional activator when bound to an RNA structure (TAR) present at the extreme 5' terminus of viral mRNA. Since transcriptional activation requires binding of Tat to RNA, it has been suggested that Tat enhances initiation or elongation through a direct interaction with cellular transcription factors. Here we show through protein fusion experiments that the previously identified cellular Tat binding protein, TBP-1, although unable to bind DNA, is a strong transcriptional activator when brought into proximity of several promoter elements. Transcriptional activity depends upon the integrity of at least two highly conserved domains: one resembling a nucleotide-binding motif and the other motif common to proteins with helicase activity. Our studies further reveal that TBP-1 represents one member of a large, highly conserved gene family that encodes proteins demonstrating strong amino acid conservation across species. Finally, we identified a second family member that, although 77% similar to TBP-1, does not activate transcription from the promoters examined. This finding, together with the observation that TBP-1 does not activate each promoter examined, suggests that this gene family may encode promoter-specific transcriptional activators.
Tissue-based map of the human proteome (2015)

Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.
Anticancer Agents: Tumor Cell Growth Inhibitory Activity and Binary QSAR Analysis (2004)

The tumor cell growth inhibitory activities (log 1/GI(50)) of 166 anticancer agents studied at the National Cancer Institute (NCI) in vitro anticancer screening program have allowed us to analyze the relative importance of physicochemical parameters in influencing the inhibitory activities. Increased molecular weight, as measured by the logarithm of molecular weight (log MW), is found to be an important contributor to the tumor cell growth inhibitory activities. The tumor cell growth inhibitory activities in different subpanels of the tumor cells are highly inter-correlated with each other. A simple binary quantitative structure-activity relationship (QSAR) model was derived from the 166 anticancer drugs, based on the tumor cell growth inhibitory activities transformed into a binary (active or inactive) data format. The model obtained can be tested with additional new data, and may be useful to identify active compounds from a large compound library to be included in high throughput screening.
The development of dermatitis infiltrated by γδ T cells in IL-7 transgenic mice (1993)

Transgenic mice constitutively expressing IL-7 developed severe dermatitis with erythroderma and alopecia. The skin lesions were characterized by massive infiltration of mononuclear cells. Immunofluorescence staining showed that most of the infiltrating cells were T cells with the majority bearing the gamma delta TCR other than the V gamma 5 moiety. Furthermore, the number of gamma delta T cells had increased in the lymphoid organs of the dermatitis animals. These findings indicate the strong relationship between the expression of IL-7 and the development of gamma delta T cells in vivo and the pathological involvement of proliferated and/or activated gamma delta T cells in skin disease.
Direct measurement of free radical generation following reperfusion of ischemic myocardium. (1987)

Electron paramagnetic resonance spectroscopy was used to directly measure free radical generation in perfused rabbit hearts. Hearts were freeze-clamped at 77 degrees K during control perfusion, after 10 min of normothermic global ischemia (no coronary flow), or following post-ischemic reperfusion with oxygenated perfusate. The spectra of these hearts exhibited three different signals with different power saturation and temperature stability: signal A was isotropic with g = 2.004; signal B was anisotropic with axial symmetry with g parallel = 2.033 and g perpendicular = 2.005; signal C was an isotropic triplet with g = 2.000 and hyperfine splitting an = 24 G (1 G = 0.1 mT). The g values, linewidth, power saturation, and temperature stability of signal A are identical to those of a carbon-centered semiquinone, whereas those of signal B are similar to alkyl peroxyl or superoxide oxygen-centered free radicals; signal C is most likely a nitrogen-centered free radical. In the control heart samples signal A predominated, whereas in ischemic hearts signal A decreased in intensity, and signals B and C became more intense; with reperfusion all three signals markedly increased. Free radical concentrations derived from the intensities of the B and C signals peaked 10 sec after initiation of reflow. At this time the oxygen-centered free radical concentration derived from the intensity of signal B was increased over six times the concentration measured in control hearts and over two times the concentration measured in ischemic hearts. Hypoxic reperfusion did not increase any of the free radical signals over the levels observed during ischemia. These experiments directly demonstrate that reactive oxygen-centered free radicals are generated in hearts during ischemia and that a burst of oxygen radical generation occurs within moments of reperfusion.
Low‐Temperature Synthesis of Single‐Crystal Germanium Nanowires by Chemical Vapor Deposition (2002)

Live-wire potential: Low-temperature growth of Ge nanowires has been achieved by the chemical vapor deposition of GeH4 onto a SiO2 substrate coated with Au nanoparticles (see picture). This technique, which represents the mildest growth conditions for single-crystal nanowire synthesis, can also be used for patterned growth processes. Under such conditions, the growth of high-quality nanowires on a variety of substrates is possible, which may yield many possibilities in nanotechnological applications.
Biochemical and Proteomic Analysis of the Magnetosome Membrane in Magnetospirillum gryphiswaldense (2004)

We analyzed the biochemical composition of the magnetosome membrane (MM) in Magnetospirillum gryphiswaldense. Isolated magnetosomes were associated with phospholipids and fatty acids which were similar to phospholipids and fatty acids from other subcellular compartments (i.e., outer and cytoplasmic membranes) but were present in different proportions. The binding characteristics of MM-associated proteins were studied by selective solubilization and limited proteolysis. The MM-associated proteins were further analyzed by various proteomic approaches, including one- and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Edman and mass spectrometric (electrospray ionization-mass spectrometry-mass spectrometry) sequencing, as well as capillary liquid chromatography-mass spectrometry-mass spectrometry of total tryptic digests of the MM. At least 18 proteins were found to constitute the magnetosome subproteome, and most of these proteins are novel for M. gryphiswaldense. Except for MM22 and Mms16, all bona fide MM proteins (MMPs) were encoded by open reading frames in the mamAB, mamDC, and mms6 clusters in the previously identified putative magnetosome island. Eight of the MMPs display homology to known families, and some of them occur in the MM in multiple homologues. Ten of the MMPs have no known homologues in nonmagnetic organisms and thus represent novel, magnetotactic bacterium-specific protein families. Several MMPs display repetitive or highly acidic sequence patterns, which are known from other biomineralizing systems and thus may have relevance for magnetite formation.