gebhart/patrepeval huggingface dataset:
Calcium Binding by Synaptotagmin's C2A Domain is an Essential Element of the Electrostatic Switch That Triggers Synchronous Synaptic Transmission (2012)

Synaptotagmin is the major calcium sensor for fast synaptic transmission that requires the synchronous fusion of synaptic vesicles. Synaptotagmin contains two calcium-binding domains: C2A and C2B. Mutation of a positively charged residue (R233Q in rat) showed that Ca2+-dependent interactions between the C2A domain and membranes play a role in the electrostatic switch that initiates fusion. Surprisingly, aspartate-to-asparagine mutations in C2A that inhibit Ca2+ binding support efficient synaptic transmission, suggesting that Ca2+ binding by C2A is not required for triggering synchronous fusion. Based on a structural analysis, we generated a novel mutation of a single Ca2+-binding residue in C2A (D229E in Drosophila) that inhibited Ca2+ binding but maintained the negative charge of the pocket. This C2A aspartate-to-glutamate mutation resulted in ∼80% decrease in synchronous transmitter release and a decrease in the apparent Ca2+ affinity of release. Previous aspartate-to-asparagine mutations in C2A partially mimicked Ca2+ binding by decreasing the negative charge of the pocket. We now show that the major function of Ca2+ binding to C2A is to neutralize the negative charge of the pocket, thereby unleashing the fusion-stimulating activity of synaptotagmin. Our results demonstrate that Ca2+ binding by C2A is a critical component of the electrostatic switch that triggers synchronous fusion. Thus, Ca2+ binding by C2B is necessary and sufficient to regulate the precise timing required for coupling vesicle fusion to Ca2+ influx, but Ca2+ binding by both C2 domains is required to flip the electrostatic switch that triggers efficient synchronous synaptic transmission.
Stereocontrolled total synthesis of 1.alpha.,25-dihydroxycholecalciferol and 1.alpha.,25-dihydroxyergocalciferol (1986)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStereocontrolled total synthesis of 1.alpha.,25-dihydroxycholecalciferol and 1.alpha.,25-dihydroxyergocalciferolEnrico G. Baggiolini, Jerome A. Iacobelli, Bernard M. Hennessy, Andrew D. Batcho, John F. Sereno, and Milan R. UskokovicCite this: J. Org. Chem. 1986, 51, 16, 3098–3108Publication Date (Print):August 1, 1986Publication History Published online1 May 2002Published inissue 1 August 1986https://pubs.acs.org/doi/10.1021/jo00366a004https://doi.org/10.1021/jo00366a004research-articleACS PublicationsRequest reuse permissionsArticle Views1762Altmetric-Citations209LEARN 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
Microflora of the Gastrointestinal Tract: A Review (2004)

The mucosal surface of the human gastrointestinal (GI) tract is about 200-300 m2 and is colonized by 1013-14 bacteria of 400 different species and subspecies. Savage has defined and categorized the gastrointestinal microflora into two types, autochthonous flora (indigenous flora) and allochthonous flora (transient flora). Autochthonous microorganisms colonize particular habitats, i.e., physical spaces in the GI tract, whereas allochthonous microorganisms cannot colonize particular habitats except under abnormal conditions. Most pathogens are allochthonous microorganisms; nevertheless, some pathogens can be autochthonous to the ecosystem and normally live in harmony with the host, except when the system is disturbed. The prevalence of bacteria in different parts of the GI tract appears to be dependent on several factors, such as pH, peristalsis, redox potential, bacterial adhesion, bacterial cooperation, mucin secretion, nutrient availability, diet, and bacterial antagonism. Because of the low pH of the stomach and the relatively swift peristalsis through the stomach and the small bowel, the stomach and the upper two-thirds of the small intestine (duodenum and jejunum) contain only low numbers of microorganisms, which range from 103 to 104 bacteria/mL of the gastric or intestinal contents, mainly acid-tolerant lactobacilli and streptococci. In the distal small intestine (ileum), the microflora begin to resemble those of the colon, with around 107-108 bacteria/mL of the intestinal contents. With decreased peristalsis, acidity, and lower oxidation-reduction potentials, the ileum maintains a more diverse microflora and a higher bacterial population. Probably because of slow intestinal motility and very low oxidation-reduction potentials, the colon is the primary site of microbial colonization in humans. The colon harbors tremendous numbers and species of bacteria. However, 99.9% of colonic microflora are obligate anaerobes.
Biochemical characterization of GSK461364: A novel, potent, and selective inhibitor of Polo-like kinase-1 (Plk1) (2007)

3257 Polo-like kinases are evolutionarily conserved ser/thr kinases that play critical roles in regulating mitosis in diverse organisms from yeast to mammalian cells. In human cells, Polo-like kinase-1 (Plk1) has been implicated in a variety of different processes, including mitotic entry, spindle formation and cytokinesis. Overexpression of Plk1 is strongly associated with cancer and correlates with poor prognosis in some tumor types, and it is therefore a target of chemotherapeutic intervention. We have identified GSK461364 as a novel thiophene amide inhibitor of Plk1 which has excellent potency against a variety of tumor cell lines, is efficacious in PD models, and shows in vivo tumor inhibition in animal models. In order to interrogate the affinity and kinetics of this inhibitor, we developed and characterized a catalytic activity assay for full length Plk1 by formation of a complex with a polobox domain binding phospho-peptide. Under these assay conditions, GSK461364 was found to be a potent, ATP-competitive inhibitor of full length Plk1 enzyme with a Ki of 2.2 ± 0.6 nM. When evaluated against full-length Plk2 and Plk3, the inhibitor exhibited approximately 400-fold greater potency for Plk1. When tested against a panel of 48 additional kinases, it was at least 100-fold selective for Plk1. GSK461364 was also found to form a rapidly reversible complex with Plk1. Our data suggest that the excellent cellular activity and in vivo efficacy demonstrated by this compound is a result of the potent and selective inhibition of Plk1, and support the advancement of GSK461364 as a novel Plk1 inhibitor for the treatment of cancer.
6-Mercaptopurine in the Management of Inflammatory Bowel Disease: Short- and Long-Term Toxicity (1989)

We assess toxicity related to 6-mercaptopurine in the treatment of inflammatory bowel disease by reporting our experience with 396 patients (120 patients with ulcerative colitis, 276 with Crohn disease) observed over 18 years. Follow-up data for a mean period of 60.3 months were obtained for 90% of the patients. Toxicity directly induced by 6-mercaptopurine included pancreatitis in 13 patients (3.3%), bone marrow depression in 8 (2%), allergic reactions in 8 (2%), and drug hepatitis in 1 (0.3%). These complications were reversible in all cases with no mortality. Most cases of marrow depression occurred earlier in our experience, when the initial drug doses used were higher. Infectious complications were seen in 29 patients (7.4%), of which 7 (1.8%) were severe, including one instance of herpes zoster encephalitis. All infections were reversible with no deaths. Twelve neoplasms (3.1%) were observed, but only 1 (0.3%), a diffuse histiocytic lymphoma of the brain, had a probable association with the use of 6-mercaptopurine. Our data, showing a low incidence of toxicity in 396 patients, coupled with the previously demonstrated efficacy of 6-mercaptopurine in the treatment of inflammatory bowel disease, indicate that the drug is a reasonable alternative in the management of patients with intractable inflammatory bowel disease.
Technetium-99m methoxyisobutylisonitrile chest imaging of small cell lung carcinoma (1998)

Tc-99m MIBI chest images have the potential to demonstrate mdr-PgP expression in SCLC and to predict patient prognosis and chemotherapy response.
Chromosome painting and quantitative karyotyping of colon adenocarcinoma cell lines, DLD-1 and HCT-15. (1994)

Chromosome painting by fluorescence in situ hybridization (FISH) was used to examine abnormalities identified by G-banding in colon cancer lines, DLD-1 (ATCC CCL 221) and HCT-15 (CCL 225). DNA libraries from chromosomes comprising these abnormalities (i.e., N2, N8, N11, N16, N17 and N20) were used to prepare paint probes by PCR amplification. Of these paint probes, N2 and N8 exhibited additional chromosome-specific hybridization signals on centromeres that were also useful as a marker for chromosome identification. Results from FISH-painting and G-band analysis were consistent and permitted our quantitative analysis on karyotype evolution in vitro. In DLD-1, predominant cells having trisomic N20 in early passages were replaced by others with disomic N20 in late passages resulting in the trisomic 2p13-23 segment as the only deviation from the diploid content. In HCT-15, predominant cells having t(16;16) and double Y chromosome copies in early passages were replaced by those bearing the paired N16 and single Y chromosome in later passages. Thus cultures changed from the predominant hyperdiploidy to the sole pseudodiploidy with increased number of normal chromosomes.
Morphologic and phenotypic features of the subpopulation of Leu-2+ cells that suppresses B cell differentiation. (1984)

The Leu-2 antigen is expressed on a subpopulation of human T cells that perform suppressor and cytotoxic functions. In addition, this antigen is also present on a portion of cells with morphologic characteristics of granular lymphocytes. Although both Leu-2+ cells and granular lymphocytes have been shown to suppress B cell differentiation, the interrelationship of these two suppressor populations has not previously been fully characterized. We recently produced a monoclonal antibody, termed D12 (anti-Leu-15), which reacts with a variety of cell types, including a subpopulation of Leu-2+ cells. Previous studies have indicated that the Leu-2+ cells that suppress T cell proliferative responses express the Leu-2+15+ phenotype, whereas the precursor and effector cytotoxic T cells that recognize class I major histocompatibility antigens are Leu-2+15- lymphocytes. For this report, we used the anti-Leu-2 and anti-Leu-15 monoclonal antibodies and fluorescence-activated cell sorter techniques to characterize the E+ cells that suppress PWM-induced B cell differentiation. These studies indicate that the vast majority of Leu-2+ cells that suppress this T cell-dependent B cell response have the Leu-2+15+ phenotype. Furthermore, when the morphologic and cytochemical characteristics of these Leu-2+15+ cells were studied, virtually all of these cells were granular lymphocytes. Most of the Leu-2+15+ suppressor cells co-expressed the HNK-1 (Leu-7) antigen, which is detected only on granular lymphocytes. In contrast, virtually none of the Leu-2+15+ granular lymphocytes expressed Fc receptors for IgG molecules. These data indicate that the Leu-2+ cells that suppress PWM-induced B cell differentiation are Leu-2+15+ (and predominantly Leu-7+) granular lymphocytes that do not express Fc receptors. The implications of these observations concerning the relationship of human Leu-2+ suppressor cells to murine Ly-2+ cells and the lineage of granular lymphocytes are discussed.
What's in a picture? The temptation of image manipulation (2004)

It's all so easy with Photoshop[1][1]. In the days before imaging software became so widely available, making adjustments to image data in the darkroom required considerable effort and/or expertise. It is now very simple, and thus tempting, to adjust or modify digital image files. Many such
Determination of Ribonuclease H Surface Enzyme Kinetics by Surface Plasmon Resonance Imaging and Surface Plasmon Fluorescence Spectroscopy (2005)

The kinetics of the ribonuclease H (RNase H) surface hydrolysis of RNA-DNA heteroduplexes formed on DNA microarrays was studied using a combination of real-time surface plasmon resonance imaging (SPRI) and surface plasmon fluorescence spectroscopy (SPFS). Time-dependent SPRI and SPFS data at various enzyme concentrations were quantitatively analyzed using a simple model that couples diffusion, enzyme adsorption, and surface enzyme kinetics. This model is characterized by a set of three rate constants, enzyme adsorption (k(a)), enzyme desorption (k(d)), enzyme catalysis (k(cat)), and one dimensionless diffusion parameter (beta). Values of k(a) = 3.15 (+/-0.20) x 10(6) M(-1).s(-1), k(d) = 0.10 (+/-0.05) s(-1), and k(cat) = 0.95 (+/-0.10) s(-1) were determined from fitting all of the SPRI and SPFS data sets. One of the most interesting kinetic parameters is the surface RNase H hydrolysis reaction rate constant (k(cat)), which was found to be approximately 10 times slower than that observed in solution, but approximately 100 times faster than that recently observed for the exonuclease III surface hydrolysis of double-stranded DNA microarrays (k(cat) = 0.009 s(-1)). Moreover, the surface coverage of the intermediate enzyme-substrate complex (ES) was found to be extremely small during the course of the reaction because k(cat) is much larger than the product of k(a) and the bulk enzyme concentration.
Organometallic VPE Growth of InAs1-xSbxon InAs (1980)

InAs1-xSbx vapor phase epitaxial growth was carried out on InAs substrate using triethylindium, triethylantimony and arsine. The vapor-solid distribution relations for the group V elements were obtained. A simplified formula for the distribution relation, which assumes thermodynamical equilibrium, is presented. The calculated distribution relation was fitted with experimental results. To study the lattice deformations rocking-curve measurements were made using X-ray double-crystal diffraction for (004) and (115) planes. The lattice distortion gradually decreased with increasing lattice mismatch up to 7 %, and cross-hatched surfaces were also observed in this region.
Abstract LB-256: Optimal clinical dose-finding strategies: Translational preclinical pharmacokineitcs, pharmacodynamics, and efficacy analysis of HM61713, an orally selective EGFR mutant inhibitor (2015)

Abstract The first-generation of EGFR1 inhibitors (Gefitinib and Erlotinib) has significant clinical benefits in NSCLC caused by activating mutations, but the efficacy of these agents is often limited due to the emergence of drug resistance conferred by a gatekeeper residue, T790M. HM61713 is a third-generation EGFR tyrosine kinase inhibitor that has been evaluated as a novel therapeutic agent for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. HM61713 is an orally active and a novel EGFR mutant selective inhibitor which is potent on resistance mutation (T790M) without affecting EGFR wild type at efficacious dose level. HM61713 showed an anti-cancer activity in several EGFR mutant lung cancer cell lines including T790M mutation harboring cell line. Integrated pharmacokinetic - pharmacodynamic - xenograft tumor model (PK-PD-XTG) was used to characterize the relationship between HM61713 plasma concentration and tumor growth inhibition (TGI) in H1975 (T790M mutation) xenograft model. Simple one-compartment model applied re-absorption compartment with first-order absorption/elimination was used to describe HM61713 plasma concentration-time profiles. Biophase distribution model with baseline inhibition Emax equation was applied to characterize the PD marker (p-EGFR) and tumor volume shrinkage was explained by michaelis-menten kinetics of p-EGFR. Estimated in vivo IC50 value of p-EGFR inhibition (%) based on plasma free concentration in xenograft mice was 1.14 ng/mL. The human PD marker response curve and the tumor growth inhibition plot were obtained by replacing the mice PK to human PK in our developed model based on the hypothesis thattranslation providesa good relationship of surrogate mice tumor PD to human tumor regression corresponding human PK. According to our simulated curves, we predicted appropriate human active dose from 300 to 800 mg/man and it would be an efficacious dose in patients with NSCLC harboring the EGFR activating and also with T790M resistant mutation. Currently, HM61713 is undergoing in clinical trial phase I/II in NSCLC (ClinicalTrials.gov, NCT01588145). Citation Format: Jooyun Byun, Taehun Song, Donghyun Kim, Junhyeng Son, Kwang-Ok Lee, Jaeho Lee, Yong Hoon Kim, Young-Mi Lee, Kwee Hyun Suh. Optimal clinical dose-finding strategies: Translational preclinical pharmacokineitcs, pharmacodynamics, and efficacy analysis of HM61713, an orally selective EGFR mutant inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-256. doi:10.1158/1538-7445.AM2015-LB-256
Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies (2006)

Inhibitory immune response to exogenously infused factor VIII (FVIII) is a major complication in the treatment of hemophilia A. Generation of such inhibitors has the potential to disrupt gene therapy for hemophilia A. We explore what we believe to be a novel approach to overcome this shortcoming. Human B-domain-deleted FVIII (hBDDFVIII) was expressed under the control of the platelet-specific alphaIIb promoter in platelets of hemophilic (FVIIInull) mice to create 2bF8trans mice. The FVIII transgene product was stored in platelets and released at the site of platelet activation. In spite of the lack of FVIII in the plasma of 2bF8trans mice, the bleeding phenotype of FVIIInull mice was corrected. More importantly, the bleeding phenotype was corrected in the presence of high inhibitory antibody titers introduced into the mice by infusion or by spleen cell transfer from recombinant hBDDFVIII-immunized mice. Our results demonstrate that this approach to the targeted expression of FVIII in platelets has the potential to correct hemophilia A, even in the presence of inhibitory immune responses to infused FVIII.
Characterization of inositol 1,4,5-trisphosphate receptors and calcium mobilization in a hepatic plasma membrane fraction. (1988)

The distribution of hepatic binding sites for the calcium-mobilizing second messenger, inositol 1,4,5-trisphosphate (IP3), was analyzed in subcellular fractions of the rat liver by binding studies with [32P]IP3 and compared with the Ca2+ release elicited by IP3 in each fraction. Three major subcellular fractions enriched in plasma membrane, mitochondria, and endoplasmic reticulum were characterized for their 5'-nucleotidase, glucose-6-phosphatase, succinate reductase, and angiotensin II binding activities. The fraction enriched in plasma membrane showed 7- and 20-fold increases in IP3 binding capacity over those enriched in endoplasmic reticulum and mitochondria, respectively, and contained a single class of high-affinity binding sites with Kd of 1.7 +/- 1.0 nM and concentration of 239 +/- 91 fmol/mg protein. IP3 binding reached equilibrium in 30 min at 0 degrees C, and the half-time of dissociation was about 15 min. The specificity of the IP3 binding sites was indicated by their markedly lower affinities for inositol 1-phosphate, phytic acid, fructose 1,6-bisphosphate, 2,3-bisphosphoglycerate, and inositol 1,3,4,5-tetrakisphosphate. The Ca2+-releasing activity of IP3 in the subcellular fractions was monitored with the fluorescent indicator, Fura-2. All three fractions showed ATP-dependent Ca2+ uptake and rapidly released Ca2+ in response in IP3. The fraction enriched in plasma membrane was the most active in this regard, releasing 174 +/- 67 pmol Ca2+/mg of protein compared to 45 +/- 10 and 48 +/- 7 pmol/mg protein for the fractions enriched in endoplasmic reticulum and mitochondria, respectively. These data suggest that the [32P]IP3 binding sites represent specific intracellular receptors through which IP3 mobilizes Ca2+ from a storage site associated (or co-purifying) with the plasma membrane of the rat liver. It is likely that a specialized vesicular system (to which IP3 can bind and trigger the release of Ca2+) is located in close proximity with the plasma membrane and is thus adjacent to the site at which IP3 is produced during stimulation of the hepatocyte by Ca2+-mobilizing hormones.
Diels--Alder reaction of .alpha.,.beta.-unsaturated trihalosilanes with cyclopentadiene (1971)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDiels--Alder reaction of .alpha.,.beta.-unsaturated trihalosilanes with cyclopentadieneRobert F. CunicoCite this: J. Org. Chem. 1971, 36, 7, 929–932Publication Date (Print):April 1, 1971Publication History Published online1 May 2002Published inissue 1 April 1971https://pubs.acs.org/doi/10.1021/jo00806a015https://doi.org/10.1021/jo00806a015research-articleACS PublicationsRequest reuse permissionsArticle Views332Altmetric-Citations53LEARN 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
Practical arc-flash reduction (2006)

This article will discuss various methods that have been used to reduce the incident energy levels in an existing electrical system is to review and modify the overcurrent protection settings. Specific solutions implemented at a large chemical manufacturing facility are presented. The solutions include equipment upgrades, overcurrent protection modifications, changes to work methods, and worker training which increase the effectiveness of an already robust safety program.