Regulation of Phosphatidylinositol 4-kinase Activity in Rat Pancreatic Acini

The present report describes the characteristics and regulatory properties of phosphatidylinositol (Ptdlns) 4-kinase activity in rat exocrine pancreas. The membrane associated Ptdlns 4-kinase displayed a broad pH profile with optimal activity at neutral to alkaline pH. Carbachol (CCh) elicits a concentration- and time-dependent increase in Ptdlns 4-kinase activity in homogenates derived from agonist-stimulated acini. This effect was blocked by N-methylscopolamine and mimicked by muscarine. The enzyme had an apparent Km for Ptdlns and ATP of 4 and 60 uM, respectively. CCh caused no discernible change in the Km for either Ptdlns or ATP, but did produce a modest increase in the Vmax. The cell permeable diacylglycerol analogues dioctanoylglycerol (DiC8) and oleoyl acetylglycerol (OAG) also produced a concentration-dependent increase in Ptdins 4-kinase activity which was blocked by the protein kinase c inhibitor, staurosporine. Cell permeable monobutyryl cAMP caused an increase in PtdIns 4-kinase activity when added to intact acini. This agent caused a significant decrease in the apparent Km for ATP but had no effect on PtdIns utilization or the Vmax of the reaction. Moreover, pretreatment of the acinar homogenate with the catalytic subunit of protein kinase A (PKA) produced a concentration-dependent increase in enzyme activity suggesting that phosphorylation may be involved in the regulation of Ptdins 4-kinase. Epidermal growth factor (EGF) elicited a concentration-dependent increase in PtdIns 4-kinase activity in homogenates derived from agonist-stimulated pancreatic acini. The combination of CCh and EGF produced a response which was not synergistic or additive. EGF, unlike CCh, failed to cause [32^P]Ptdins(4,5)P2 breakdown, suggesting different mechanisms for the increase in Ptdins 4-kinase activity induced by EGF and CCh. Furthermore, exposure of pancreatic acinar cells to EGF failed to elevate cyclic AMP levels, suggesting that a third pathway exists for the regulation of Ptdins 4-kinase activity in the exocrine pancreas. We conclude that PtdIns 4-kinase represents a key component of the signaling pathways utilized by various receptor agonists and that phosphoinositide synthesis is under direct and tight regulation by PKC- and PKA-dependent pathways

Interactions of Cbl with Grb2 and phosphatidylinositol 3\u27-kinase in activated Jurkat cells

T-cell receptor (TCR) cross-linking increases tyrosine phosphorylation of multiple proteins, only a few of which have been identified. One of the most rapidly tyrosine-phosphorylated polypeptides is the 120-kDa product of the proto-oncogene c-cbl, a cytosolic and cytoskeletal protein containing multiple proline-rich motifs that are potential binding sites for proteins containing Src homology 3 (SH3) domains. We report here that in cultured Jurkat T cells, Cbl is coprecipitated with antibody against the adapter protein Grb2. Upon activation of Jurkat T cells via the TCR-CD3 complex, we find that high-affinity binding of Cbl requires the N-terminal SH3 domain of GST-Grb2 fusion protein but after cross-linking of the TCR-CD3 and CD4 receptors, Cbl binds equally to its SH2 domain. Grb2 antisera also precipitated p85 from serum-starved cells, while TCR activation increased p85 and tyrosine-phosphorylated Cbl but not Cbl protein in Grb2 immunocomplexes. Phosphatidylinositol (PI) 3-kinase activity was immunoprecipitated from serum-starved cells with Cbl and to a lesser extent with Grb2 antisera, and TCR cross-linking increased this activity severalfold. The PI 3-kinase activity associated with Cbl amounted to 5 to 10% of the total cellular activity that could be precipitated by p85 antisera. The Ras exchange factor Son-of-sevenless 1 (Sos-1) was not found in anti-Cbl immunoprecipitates from activated cells, and Cbl was not detectable in anti-Sos-1 precipitates, supporting the likelihood that Sos-Grb2 and Cbl-Grb2 are present as distinct complexes. Taken together, these data suggest that Cbl function in Jurkat T cells involves its constitutive association with Grb2 and its recruitment of PI 3-kinase in response to TCR activation

Conformal Field Theories, Representations and Lattice Constructions

An account is given of the structure and representations of chiral bosonic meromorphic conformal field theories (CFT's), and, in particular, the conditions under which such a CFT may be extended by a representation to form a new theory. This general approach is illustrated by considering the untwisted and $Z_2$-twisted theories, $H(\Lambda)$ and $\tilde H(\Lambda)$ respectively, which may be constructed from a suitable even Euclidean lattice $\Lambda$. Similarly, one may construct lattices $\Lambda_C$ and $\tilde\Lambda_C$ by analogous constructions from a doubly-even binary code $C$. In the case when $C$ is self-dual, the corresponding lattices are also. Similarly, $H(\Lambda)$ and $\tilde H(\Lambda)$ are self-dual if and only if $\Lambda$ is. We show that $H(\Lambda_C)$ has a natural ``triality'' structure, which induces an isomorphism $H(\tilde\Lambda_C)\equiv\tilde H(\Lambda_C)$ and also a triality structure on $\tilde H(\tilde\Lambda_C)$. For $C$ the Golay code, $\tilde\Lambda_C$ is the Leech lattice, and the triality on $\tilde H(\tilde\Lambda_C)$ is the symmetry which extends the natural action of (an extension of) Conway's group on this theory to the Monster, so setting triality and Frenkel, Lepowsky and Meurman's construction of the natural Monster module in a more general context. The results also serve to shed some light on the classification of self-dual CFT's. We find that of the 48 theories $H(\Lambda)$ and $\tilde H(\Lambda)$ with central charge 24 that there are 39 distinct ones, and further that all 9 coincidences are accounted for by the isomorphism detailed above, induced by the existence of a doubly-even self-dual binary code.Comment: 65 page

Comparative population structure of <i>Plasmodium malariae</i> and <i>Plasmodium falciparum</i> under different transmission settings in Malawi

&lt;b&gt;Background:&lt;/b&gt; Described here is the first population genetic study of Plasmodium malariae, the causative agent of quartan malaria. Although not as deadly as Plasmodium falciparum, P. malariae is more common than previously thought, and is frequently in sympatry and co-infection with P. falciparum, making its study increasingly important. This study compares the population parameters of the two species in two districts of Malawi with different malaria transmission patterns - one seasonal, one perennial - to explore the effects of transmission on population structures. &lt;BR/&gt; &lt;b&gt;Methods:&lt;/b&gt; Six species-specific microsatellite markers were used to analyse 257 P. malariae samples and 257 P. falciparum samples matched for age, gender and village of residence. Allele sizes were scored to within 2 bp for each locus and haplotypes were constructed from dominant alleles in multiple infections. Analysis of multiplicity of infection (MOI), population differentiation, clustering of haplotypes and linkage disequilibrium was performed for both species. Regression analyses were used to determine association of MOI measurements with clinical malaria parameters. &lt;BR/&gt; &lt;b&gt;Results:&lt;/b&gt; Multiple-genotype infections within each species were common in both districts, accounting for 86.0% of P. falciparum and 73.2% of P. malariae infections and did not differ significantly with transmission setting. Mean MOI of P. falciparum was increased under perennial transmission compared with seasonal (3.14 vs 2.59, p = 0.008) and was greater in children compared with adults. In contrast, P. malariae mean MOI was similar between transmission settings (2.12 vs 2.11) and there was no difference between children and adults. Population differentiation showed no significant differences between villages or districts for either species. There was no evidence of geographical clustering of haplotypes. Linkage disequilibrium amongst loci was found only for P. falciparum samples from the seasonal transmission setting. &lt;BR/&gt; &lt;b&gt;Conclusions:&lt;/b&gt; The extent of similarity between P. falciparum and P. malariae population structure described by the high level of multiple infection, the lack of significant population differentiation or haplotype clustering and lack of linkage disequilibrium is surprising given the differences in the biological features of these species that suggest a reduced potential for out-crossing and transmission in P. malariae. The absence of a rise in P. malariae MOI with increased transmission or a reduction in MOI with age could be explained by differences in the duration of infection or degree of immunity compared to P. falciparum

Regular breakfast consumption and type 2 diabetes risk markers in 9- to 10-year-old children in the child heart and health study in England (CHASE): a cross-sectional analysis.

BACKGROUND: Regular breakfast consumption may protect against type 2 diabetes risk in adults but little is known about its influence on type 2 diabetes risk markers in children. We investigated the associations between breakfast consumption (frequency and content) and risk markers for type 2 diabetes (particularly insulin resistance and glycaemia) and cardiovascular disease in children. METHODS AND FINDINGS: We conducted a cross-sectional study of 4,116 UK primary school children aged 9-10 years. Participants provided information on breakfast frequency, had measurements of body composition, and gave fasting blood samples for measurements of blood lipids, insulin, glucose, and glycated haemoglobin (HbA1c). A subgroup of 2,004 children also completed a 24-hour dietary recall. Among 4,116 children studied, 3,056 (74%) ate breakfast daily, 450 (11%) most days, 372 (9%) some days, and 238 (6%) not usually. Graded associations between breakfast frequency and risk markers were observed; children who reported not usually having breakfast had higher fasting insulin (percent difference 26.4%, 95% CI 16.6%-37.0%), insulin resistance (percent difference 26.7%, 95% CI 17.0%-37.2%), HbA1c (percent difference 1.2%, 95% CI 0.4%-2.0%), glucose (percent difference 1.0%, 95% CI 0.0%-2.0%), and urate (percent difference 6%, 95% CI 3%-10%) than those who reported having breakfast daily; these differences were little affected by adjustment for adiposity, socioeconomic status, and physical activity levels. When the higher levels of triglyceride, systolic blood pressure, and C-reactive protein for those who usually did not eat breakfast relative to those who ate breakfast daily were adjusted for adiposity, the differences were no longer significant. Children eating a high fibre cereal breakfast had lower insulin resistance than those eating other breakfast types (p for heterogeneity <0.01). Differences in nutrient intakes between breakfast frequency groups did not account for the differences in type 2 diabetes markers. CONCLUSIONS: Children who ate breakfast daily, particularly a high fibre cereal breakfast, had a more favourable type 2 diabetes risk profile. Trials are needed to quantify the protective effect of breakfast on emerging type 2 diabetes risk. Please see later in the article for the Editors' Summary

Discovery of (R)-2-Amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic Acid and Congeners As Highly Potent Inhibitors of Human Arginases I and II for Treatment of Myocardial Reperfusion Injury

Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure−activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.Fil: Van Zandt, Michael C.. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Whitehouse, Darren L.. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Golebiowski, Adam. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Ji, Min Koo. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Zhang, Mingbao. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Beckett, R. Paul. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Jagdmann, G. Erik. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Ryder, Todd R.. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Sheeler, Ryan. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Andreoli, Monica. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Conway, Bruce. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Mahboubi, Keyvan. Institutes for Pharmaceutical Discovery; Estados UnidosFil: D’Angelo, Gerard. Institutes for Pharmaceutical Discovery; Estados UnidosFil: Mitschler, Andre. Université de Strasbourg; FranciaFil: Cousido Siah, Alexandra. Université de Strasbourg; FranciaFil: Ruiz, Frances X.. Université de Strasbourg; FranciaFil: Howard, Eduardo Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Université de Strasbourg; FranciaFil: Podjarny, Alberto Daniel. Université de Strasbourg; FranciaFil: Schroeter, Hagen. Mars Incorporated; Estados Unido

Developmental Toxicity of Nicotine: A Transdisciplinary Synthesis and Implications for Emerging Tobacco Products

While the health risks associated with adult cigarette smoking have been well described, effects of nicotine exposure during periods of developmental vulnerability are often overlooked. Using MEDLINE and PubMed literature searches, books, reports and expert opinion, a transdisciplinary group of scientists reviewed human and animal research on the health effects of exposure to nicotine during pregnancy and adolescence. A synthesis of this research supports that nicotine contributes critically to adverse effects of gestational tobacco exposure, including reduced pulmonary function, auditory processing defects, impaired infant cardiorespiratory function, and may contribute to cognitive and behavioral deficits in later life. Nicotine exposure during adolescence is associated with deficits in working memory, attention, and auditory processing, as well as increased impulsivity and anxiety. Finally, recent animal studies suggest that nicotine has a priming effect that increases addiction liability for other drugs. The evidence that nicotine adversely affects fetal and adolescent development is sufficient to warrant public health measures to protect pregnant women, children, and adolescents from nicotine exposure

The largest deep-ocean silicic volcanic eruption of the past century

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Science Advances 4 (2018): e1701121, doi:10.1126/sciadv.1701121.The 2012 submarine eruption of Havre volcano in the Kermadec arc, New Zealand, is the largest deep-ocean eruption in history and one of very few recorded submarine eruptions involving rhyolite magma. It was recognized from a gigantic 400-km2 pumice raft seen in satellite imagery, but the complexity of this event was concealed beneath the sea surface. Mapping, observations, and sampling by submersibles have provided an exceptionally high fidelity record of the seafloor products, which included lava sourced from 14 vents at water depths of 900 to 1220 m, and fragmental deposits including giant pumice clasts up to 9 m in diameter. Most (>75%) of the total erupted volume was partitioned into the pumice raft and transported far from the volcano. The geological record on submarine volcanic edifices in volcanic arcs does not faithfully archive eruption size or magma production.This research was funded by Australian Research Council Postdoctoral fellowships (DP110102196 and DE150101190 to R. Carey), a short-term postdoctoral fellowship grant from the Japan Society for the Promotion of Science (to R. Carey), National Science Foundation grants (OCE1357443 to B.H., OCE1357216 to S.A.S., and EAR1447559 to J.D.L.W.), and a New Zealand Marsden grant (U001616 to J.D.L.W.). J.D.L.W. and A.M. were supported by a research grant and PhD scholarship from the University of Otago. R.W. was supported by NIWA grant COPR1802. J.D.L.W. and F.C.-T. were supported by GNS Science grants CSA-GHZ and CSA-EEZ. M.J. was supported by the U.S. Department of Defense (DoD) through the National Defense Science and Engineering Graduate Fellowship (NDSEG) Program

Exceptionally Preserved Jellyfishes from the Middle Cambrian

Cnidarians represent an early diverging animal group and thus insight into their origin and diversification is key to understanding metazoan evolution. Further, cnidarian jellyfish comprise an important component of modern marine planktonic ecosystems. Here we report on exceptionally preserved cnidarian jellyfish fossils from the Middle Cambrian (∼505 million years old) Marjum Formation of Utah. These are the first described Cambrian jellyfish fossils to display exquisite preservation of soft part anatomy including detailed features of structures interpreted as trailing tentacles and subumbrellar and exumbrellar surfaces. If the interpretation of these preserved characters is correct, their presence is diagnostic of modern jellyfish taxa. These new discoveries may provide insight into the scope of cnidarian diversity shortly after the Cambrian radiation, and would reinforce the notion that important taxonomic components of the modern planktonic realm were in place by the Cambrian period