gebhart/patrepeval huggingface dataset:
Kinetics and regulation of pantothenate kinase from Escherichia coli. (1994)

Pantothenate kinase catalyzes the rate-controlling step in coenzyme A (CoA) biosynthesis and is regulated by feedback inhibition by CoA. Pantothenate kinase was purified to homogeneity from Escherichia coli and was shown to exist as a homodimer. Kinetic analysis indicated the presence of two ATP binding sites that exhibited positive cooperativity with a Hill coefficient of 1.46. Site-directed mutagenesis of lysine 101 to methionine (K101M) resulted in the inactivation of the enzyme, although dimer formation was not altered. The K101M mutant was unable to bind either adenosine 5'-O-(3-thiotriphosphate) or CoA, supporting the conclusion from kinetic analysis that both the substrate and inhibitor bind to the same site on the enzyme. CoA binding was not cooperative. Coexpression of the K101M mutant gene on a high copy number plasmid in the presence of a chromosomal copy of the wild-type gene resulted in the production of heterodimers between active and inactive subunits. Kinetic analysis of the chimeric heterodimers showed the absence of cooperative ATP interactions and indicated a sequential kinetic mechanism for pantothenate kinase with ATP binding first and pantothenate second. Thus, pantothenate kinase regulation involves the competitive binding of CoA to the ATP site, which blocks ATP binding at one site and prevents positive cooperative ATP binding to the second site on the dimer.
Redirecting In vivo Elicited Tumor Infiltrating Macrophages and Dendritic Cells towards Tumor Rejection (2005)

A hostile tumor microenvironment interferes with the development and function of the adaptive immune response. Here we report the mechanisms by which large numbers of tumor-infiltrating macrophages and dendritic cells (DC) can be redirected to become potent effectors and activators of the innate and adaptive immunity, respectively. We use adenoviral delivery of the CCL16 chemokine to promote accumulation of macrophages and DC at the site of preestablished tumor nodules, combined with the Toll-like receptor 9 ligand CpG and with anti-interleukin-10 receptor antibody. CpG plus anti-interleukin-10 receptor antibody promptly switched infiltrating macrophages infiltrate from M2 to M1 and triggered innate response debulking large tumors within 16 hours. Tumor-infiltrating DC matured and migrated in parallel with the onset of the innate response, allowing the triggering of adaptive immunity before the diffuse hemorrhagic necrosis halted the communication between tumor and draining lymph nodes. Treatment of B6>CXB6 chimeras implanted with BALB/c tumors with the above combination induced an efficient innate response but not CTL-mediated tumor lysis. In these mice, tumor rejection did not exceed 25%, similarly to that observed in CCR7-null mice that have DC unable to prime an adaptive response. The requirement of CD4 help was shown in CD40-KO, as well as in mice depleted of CD4 T cells, during the priming rather than the effector phase. Our data describe the critical requirements for the immunologic rejection of large tumors: a hemorrhagic necrosis initiated by activated M1 macrophages and a concomitant DC migration to draining lymph nodes for subsequent CTL priming and clearing of any tumor remnants.
Pro-inflammatory Secretory Phospholipase A2 Type IIA Binds to Integrins αvβ3 and α4β1 and Induces Proliferation of Monocytic Cells in an Integrin-dependent Manner (2008)

Secretory phospholipase A2 group IIA (sPLA2-IIA) plays an important role in the pathogenesis of inflammatory diseases. Catalytic activity of this enzyme that generates arachidonic acid is a major target for development of anti-inflammatory agents. Independent of its catalytic activity, sPLA2-IIA induces pro-inflammatory signals in a receptor-mediated mechanism (e.g. through the M-type receptor). However, the M-type receptor is species-specific: sPLA2-IIA binds to the M-type receptor in rodents and rabbits, but not in human. Thus sPLA2-IIA receptors in human have not been established. Here we demonstrated that sPLA2-IIA bound to integrin alphavbeta3 at a high affinity (K(D)=2 x 10(-7) M). We identified amino acid residues in sPLA2-IIA (Arg-74 and Arg-100) that are critical for integrin binding using docking simulation and mutagenesis. The integrin-binding site did not include the catalytic center or the M-type receptor-binding site. sPLA2-IIA also bound to alpha4beta1. We showed that sPLA2-IIA competed with VCAM-1 for binding to alpha4beta1, and bound to a site close to those for VCAM-1 and CS-1 in the alpha4 subunit. Wild type and the catalytically inactive H47Q mutant of sPLA2-IIA induced cell proliferation and ERK1/2 activation in monocytic cells, but the integrin binding-defective R74E/R100E mutant did not. This indicates that integrin binding is required, but catalytic activity is not required, for sPLA2-IIA-induced proliferative signaling. These results suggest that integrins alphavbeta3 and alpha4beta1 may serve as receptors for sPLA2-IIA and mediate pro-inflammatory action of sPLA2-IIA, and that integrin-sPLA2-IIA interaction is a novel therapeutic target.
TGFβ/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells (2005)

Human embryonic stem cells (hESCs) self-renew indefinitely and give rise to derivatives of all three primary germ layers, yet little is known about the signaling cascades that govern their pluripotent character. Because it plays a prominent role in the early cell fate decisions of embryonic development, we have examined the role of TGFbeta superfamily signaling in hESCs. We found that, in undifferentiated cells, the TGFbeta/activin/nodal branch is activated (through the signal transducer SMAD2/3) while the BMP/GDF branch (SMAD1/5) is only active in isolated mitotic cells. Upon early differentiation, SMAD2/3 signaling is decreased while SMAD1/5 signaling is activated. We next tested the functional role of TGFbeta/activin/nodal signaling in hESCs and found that it is required for the maintenance of markers of the undifferentiated state. We extend these findings to show that SMAD2/3 activation is required downstream of WNT signaling, which we have previously shown to be sufficient to maintain the undifferentiated state of hESCs. Strikingly, we show that in ex vivo mouse blastocyst cultures, SMAD2/3 signaling is also required to maintain the inner cell mass (from which stem cells are derived). These data reveal a crucial role for TGFbeta signaling in the earliest stages of cell fate determination and demonstrate an interconnection between TGFbeta and WNT signaling in these contexts.
Claves para cubrir los riesgos de oscilaciones de los tipos de cambio (2009)

La ingenieria financiera proporciona un tipo especial de instrumentos financieros para la cobertura de posiciones en divisas a corto plazo. Generalmente para este tipo de operaciones suelen ser mas conocidos los swaps sobre divisas. No obstante, los FXA pretenden mejorar la eficiencia de estos contratos en situaciones especiales a menos de un ano. En el presente articulo se pretende ofrecer un ejemplo practico de la utilidad e importancia de los FXA, asi como algunas recomendaciones a tenor de los resultados obtenidos, teniendo en cuenta la relevancia de este tipo de contratos como base para otros productos financieros mas complejos, como pudiera ser el caso de los propios swaps u otros derivados OTC.
A Chimeric, Ligand-Binding v- erb B/EGF Receptor Retains Transforming Potential (1987)

Comparison of amino acid sequences from human epidermal growth factor (EGF) receptor and avian erythroblastosis virus erbB oncogene product suggests that v-erbB represents a truncated avian EGF receptor gene product. Although both proteins are transmembrane tyrosine kinases, the v-erbB protein lacks most of the extracellular ligand-binding domain and a 32-amino acid cytoplasmic sequence present in the human EGF receptor. To test the validity of the proposed origin of v-erbB and to investigate the functional significance of the deleted extracellular sequences, a chimeric gene encoding the extracellular and the transmembrane domain of the human EGF receptor joined to sequences coding for the cytoplasmic domain of the avian erbB oncogene product was constructed. When expressed in Rat1 fibroblasts, this reconstituted gene product (HER-erbB) was transported to the cell surface and bound EGF. Its autophosphorylation activity was stimulated by interaction with the ligand. Expression of the HER-erbB chimera led to anchorage-independent cell growth in soft agar and EGF-induced focus formation in Rat1 monolayers. Thus, it appears that v-erbB protein sequences in the chimeric receptor retain their transforming activity under the influence of the human extracellular EGF-binding domain.
Genome packaging in influenza A virus (2009)

The negative-sense RNA genome of influenza A virus is composed of eight segments, which encode 12 proteins between them. At the final stage of viral assembly, these genomic virion (v)RNAs are incorporated into the virion as it buds from the apical plasma membrane of the cell. Genome segmentation confers evolutionary advantages on the virus, but also poses a problem during virion assembly as at least one copy of each of the eight segments is required to produce a fully infectious virus particle. Historically, arguments have been presented in favour of a specific packaging mechanism that ensures incorporation of a full genome complement, as well as for an alternative model in which segments are chosen at random but packaged in sufficient numbers to ensure that a reasonable proportion of virions are viable. The question has seen a resurgence of interest in recent years leading to a consensus that the vast majority of virions contain no more than eight segments and that a specific mechanism does indeed function to select one copy of each vRNA. This review summarizes work leading to this conclusion. In addition, we describe recent progress in identifying the specific packaging signals and discuss likely mechanisms by which these RNA elements might operate.
Substitution of Valine for Leucine 305 in Factor VIIa Increases the Intrinsic Enzymatic Activity (2001)

Factor VII requires the cleavage of an internal peptide bond and the association with tissue factor (TF) to attain its fully active factor VIIa (FVIIa) conformation. The former event alone leaves FVIIa in a zymogen-like state of relatively low specific activity. We have designed a number of FVIIa mutants with the aim of mimicking the effect of TF, that is, creating molecules with increased intrinsic (TF-independent) enzymatic activity. Based on a possible structural difference between free and TF-bound FVIIa (Pike, A. C. W., Brzozowski, A. M., Roberts, S. M., Olsen, O. H., and Persson, E. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 8925--8930), we focused on the helical region encompassing residues 307-312 and residues in its spatial vicinity. For instance, FVIIa contains Phe-374 and Leu-305, whereas a Phe/Tyr residue in the position corresponding to 374 in homologous coagulation serine proteases is accompanied by Val in the position corresponding to 305. This conceivably results in a unique orientation of this helix in FVIIa. Substitution of Val for Leu-305 in FVIIa resulted in a 3--4-fold increase in the intrinsic amidolytic and proteolytic activity as compared with wild-type FVIIa, whereas the activity in complex with soluble TF remained the same. In accordance with this, L305V-FVIIa exhibited an increased rate of inhibition as compared with wild-type FVIIa, both by d-Phe-Phe-Arg-chloromethyl ketone and antithrombin III in the presence of heparin. The increased FVIIa activity upon replacement of Leu-305 by Val may be mediated by a movement of the 307--312 helix into an orientation resembling that found in factors IXa and Xa and thrombin. The corresponding shortening of the side chain of residue 374 (Phe --> Pro) had a smaller effect (about 1.5-fold increase) on the intrinsic activity of FVIIa. Attempts to increase FVIIa activity by introducing single or multiple mutations at positions 306, 309, and 312 to stabilize the 307-312 helix failed.
SevereDemodexfolliculorum–Associated Oculocutaneous Rosacea in a Girl Successfully Treated With Ivermectin (2013)

The causative role of Demodex folliculorum should be considered in immunocompetent children with rosacea or rosacea-like refractory eruptions. In such cases, treatment with ivermectin can be beneficial.
Preterm Labor, Intrauterine Infection, and the Fetal Inflammatory Response Syndrome (2002)

After completing this article, readers should be able to: 

1. Describe the components of the common terminal pathway of human parturition.

2. Define the preterm parturition syndrome.

3. Describe the pathways of intrauterine infection.

4. Explain the relationship between intrauterine infection and preterm birth.

5. List the organisms most frequently involved in intra-amniotic infections.

6. Describe the role of inflammation and proinflammatory cytokines in the mechanisms of parturition.

7. Describe the fetal inflammatory response syndrome and its consequences.

The implicit paradigm that has governed the clinical management and investigation of preterm parturition is that term and preterm labor are fundamentally the same processes except for the gestational age at which they occur. Indeed, term and preterm labor share a common terminal pathway composed of myometrial contractility, cervical ripening, and decidual/membrane activation (Fig. 1)⇓. Clinical tests to identify the patient at risk for preterm birth have focused on detection of premature activation of each of these components (Fig. 2)⇓. For example, uterine activity monitoring, ultrasonographic examination of the cervix, and measurement of fetal fibronectin can be used to detect myometrial activation, cervical ripening, and membrane/decidual activation, respectively. Interventions to prevent preterm birth also are also aimed at the common terminal pathway. Pharmacologic inhibition of uterine contractility (ie, tocolysis) and cervical cerclage have been proposed as methods to prevent preterm birth (Fig. 2)⇓. Antibiotic administration to patients who have positive fetal fibronectin (an indirect marker of membrane/decidual activation) has been attempted as a means of decreasing preterm birth based on the belief that a positive fibronectin finding is due to subclinical intrauterine infection. None of these interventions has proven successful.



Figure 1. 
Term and preterm labor share a common terminal pathway composed of myometrial contractility, cervical ripening, and decidual/membrane activation. MLCK=myosin light chain kinase. Modified from an original drawing of Professor Gabor Haszor, Yale University. …
A 5‐week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long‐acting glucagon‐like peptide‐1 analogue, in patients with type 2 diabetes (2011)

LY showed improvement in fasting and postprandial glycaemic parameters when administered once weekly in subjects with type 2 diabetes. The pharmacokinetics and safety profiles also support further investigation of this novel agent.
Molecular or Supramolecular Templating: Defining the Role of Surfactant Chemistry in the Formation of Microporous and Mesoporous Molecular Sieves (1994)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMolecular or Supramolecular Templating: Defining the Role of Surfactant Chemistry in the Formation of Microporous and Mesoporous Molecular SievesJ. S. Beck, J. C. Vartuli, G. J. Kennedy, C. T. Kresge, W. J. Roth, and S. E. SchrammCite this: Chem. Mater. 1994, 6, 10, 1816–1821Publication Date (Print):October 1, 1994Publication History Published online1 May 2002Published inissue 1 October 1994https://pubs.acs.org/doi/10.1021/cm00046a040https://doi.org/10.1021/cm00046a040research-articleACS PublicationsRequest reuse permissionsArticle Views2349Altmetric-Citations365LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Clinical Overview of Varicella Vaccine: Development and Early Studies (1986)

A live varicella vaccine was developed in 1973 and has been used effectively and safely in normal as well as high-risk children. Some precautions are necessary for use in the high-risk children.
Enhanced expression of p46 Shc in the nucleus and p52 Shc in the cytoplasm of human gastric cancer (2005)

Shc protein is known to be related to cell proliferation and carcinogenesis. However, the involvement of Shc in gastric cancer remains unknown. In the present study, we examined the expression and localization of Shc in human gastric cancer and the adjacent normal mucosa by Western blotting and immunohistochemical analyses. Furthermore, the expression of Shc in a gastric cancer cell line, MKN 28, was also studied. p66 Shc was not detected at all in gastric cancer or the adjacent normal mucosa. In contrast, immunohistochemical and Western blot analyses revealed that p52 Shc was detected in the cytoplasmic fractions obtained from gastric normal mucosa and cancer, while p46 Shc expression was observed in the nuclear fractions from gastric normal mucosa and cancer. Furthermore, not only p52 Shc expression in the cytoplasm but also p46 Shc expression in the nucleus was much higher in gastric cancer than in the adjacent normal mucosa. Subsequent in vitro experiments with MKN 28 gastric cancer cells also revealed that p52 Shc was expressed solely in the cytoplasm and p46 Shc was solely in the nucleus. These results suggest that the enhancement of p46 Shc and p52 Shc expression may be related to the occurrence of gastric cancer. Furthermore, unlike p52 Shc, p46 Shc was shown to be expressed solely in the nucleus, suggesting that p46 Shc expressed in the nucleus may play an important role in gastric carcinogenesis.
Expanding roles for miRNAs and siRNAs in cell regulation (2004)

The role of small RNAs as key regulators of mRNA turnover and translation has been well established. Recent advances indicate that the small RNAs termed microRNAs play important roles in cell proliferation, apoptosis and differentiation. Moreover, the microRNA mechanism is an efficient means to regulate production of a diverse range of proteins. As new microRNAs and their mRNA targets rapidly emerge, it is becoming apparent that RNA-based regulation of mRNAs may rival ubiquitination as a mechanism to control protein levels.
Diamagnetic levitation: Flying frogs and floating magnets (invited) (2000)

Contrary to our intuition, apparently nonmagnetic substances can be levitated in a magnetic field and can stabilize free levitation of a permanent magnet. Most substances are weakly diamagnetic and the tiny forces associated with this property make the two types of levitation possible. Living things mostly consist of diamagnetic molecules (such as water and proteins) and components (such as bones) and therefore can be levitated and can experience low gravity. In this way, frogs have been able to fly in the throat of a high field magnet. Stable levitation of one magnet by another with no energy input is usually prohibited by Earnshaw’s Theorem. However, the introduction of diamagnetic material at special locations can stabilize such levitation. A magnet can even be stably suspended between (diamagnetic) fingertips.
Serum Adiponectin Levels Are Inversely Associated with Overall and Central Fat Distribution but Are Not Directly Regulated by Acute Fasting or Leptin Administration in Humans: Cross-Sectional and Interventional Studies (2003)

Adiponectin is an adipocyte-secreted protein that circulates in high concentrations in the serum and acts to increase insulin sensitivity. Previous studies have shown that serum adiponectin is inversely associated with fat mass and insulin resistance in humans and that acute fasting decreases adipose tissue adiponectin mRNA expression in rodents. Whether acute energy deprivation, body fat distribution, or serum hormone levels are associated with circulating adiponectin in humans remains largely unknown. To identify predictors of serum adiponectin levels, we evaluated the association of adiponectin with several anthropometric, metabolic, and hormonal variables in a cross-sectional study of 121 women without a known history of diabetes. We also performed interventional studies to assess whether fasting for 48 h and/or leptin administration regulates serum adiponectin in healthy men and women. Our cross-sectional study shows that, in addition to overall obesity, central fat distribution is an independent negative predictor of serum adiponectin and suggests that adiponectin may represent a link between central obesity and insulin resistance. In addition, estradiol is negatively and independently associated with adiponectin, whereas there is no association between serum adiponectin and leptin, cortisol, or free testosterone levels. Our interventional studies demonstrate that neither fasting for 48 h, resulting in a low leptin state, nor leptin administration at physiological or pharmacological doses alters serum adiponectin levels. Further studies are needed to fully elucidate the physiology of adiponectin in humans and its role in the pathogenesis of insulin-resistant states.
Hyperalgesic priming in the rat demonstrates marked sexual dimorphism (2003)

In male rats, carrageenan (CAR)-induced inflammation or exposure to a selective protein kinase C epsilon (PKC epsilon ) agonist (psi epsilon RACK) produces prolongation of the hyperalgesia induced by a subsequent exposure to an inflammatory mediator, a phenomenon referred to as hyperalgesic priming. Since many chronic inflammatory conditions are sexually dimorphic, we tested the hypothesis that hyperalgesic priming is sexually dimorphic. Prior injection of CAR or psi epsilon RACK produced a prolongation of the hyperalgesia induced by a subsequent injection of prostaglandin E(2), from less than 3 h to greater than 24 h, but only in male rats. In ovariectomized female rats priming with CAR and psi epsilon RACK produced hyperalgesic priming effects similar to that observed in the male rat, and this effect was reversed by estrogen replacement. While gonadectomy in males had no effect on CAR and psi epsilon RACK induced hyperalgesic priming, female phenotype was observed following implantation of estrogen in males. Thus, mechanisms mediating the development of hyperalgesic priming produced by inflammation are suppressed by estrogen. This regulation of priming by estrogen appears to occur at or downstream of the activation of PKC epsilon.