Insulin and IGF-1 enhance the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin pathway.

MCT2 is the main neuronal monocarboxylate transporter essential for facilitating lactate and ketone body utilization as energy substrates. Our study reveals that treatment of cultured cortical neurons with insulin and IGF-1 led to a striking enhancement of MCT2 immunoreactivity in a time- and concentration-dependent manner. Surprisingly, neither insulin nor IGF-1 affected MCT2 mRNA expression, suggesting that regulation of MCT2 protein expression occurs at the translational rather than the transcriptional level. Investigation of the putative signalling pathways leading to translation activation revealed that insulin and IGF-1 induced p44- and p42 MAPK, Akt and mTOR phosphorylation. S6 ribosomal protein, a component of the translational machinery, was also strongly activated by insulin and IGF-1. Phosphorylation of p44- and p42 MAPK was blocked by the MEK inhibitor PD98058, while Akt phosphorylation was abolished by the PI3K inhibitor LY294002. Phosphorylation of mTOR and S6 was blocked by the mTOR inhibitor rapamycin. In parallel, it was observed that LY294002 and rapamycin almost completely blocked the effects of insulin and IGF-1 on MCT2 protein expression, whereas PD98059 and SB202190 (a p38K inhibitor) had no effect on insulin-induced MCT2 expression and only a slight effect on IGF-1-induced MCT2 expression. At the subcellular level, a significant increase in MCT2 protein expression within an intracellular pool was observed while no change at the cell surface was apparent. As insulin and IGF-1 are involved in synaptic plasticity, their effect on MCT2 protein expression via an activation of the PI3K-Akt-mTOR-S6K pathway might contribute to the preparation of neurons for enhanced use of nonglucose energy substrates following altered synaptic efficacy.

PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8⁺ T cells induced by melanoma vaccines.

Although melanoma vaccines stimulate tumor antigen-specific CD8(+) T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8(+) T cells with regard to the inhibitory T-cell coreceptors PD-1 and Tim-3 in patients with metastatic melanoma who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant, CpG oligodeoxynucleotide (CpG), and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid tumor antigen-specific CD8(+) T-cell responses detected ex vivo, however, tumor antigen-specific CD8(+) T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8(+) T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8(+) T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8(+) T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T-cell responses and increase the likelihood of clinical responses in patients with advanced melanoma.

D-3 Dependent Adult Abuse Report, January 1, 2014 - June 31, 2014

D-3 Dependent Adult Abuse Report

Footnotes, January, February, March 2014, Vol. 39, no. 1-3

Monthly newsletter of State Library

Iowa Ag Review, June 1995, Vol. 1, no. 3

Iowa Ag Review is a quarterly newsletter published by the Center for Agricultural and Rural Development (CARD). This publication presents summarized results that emphasize the implications of ongoing agricultural policy analysis, analysis of the near-term agricultural situation, and discussion of agricultural policies currently under consideration.

Iowa Manure Matters: Odor and Nutrient Management, Spring 2000, Vol. 3, no. 1

Iowa Manure Matters: Odor and Nutrient Management is published by Iowa State University Extension, with funding support from the USDA Natural Resource Conservation Service.

Synthesis of a non-peptidic PET tracer designed for α5β1 integrin receptor.

Arginine-glycine-aspartic acid (RGD)-containing peptides have been traditionally used as PET probes to noninvasively image angiogenesis, but recently, small selective molecules for α5 β1 integrin receptor have been developed with promising results. Sixty-one antagonists were screened, and tert-butyl (S)-3-(2-((3R,5S)-1-(3-(1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)propanoyl)-5-((pyridin-2-ylamino)methyl)pyrrolidin-3-yloxy)acetamido)-2-(2,4,6-trimethylbenzamido)propanoate (FPMt) was selected for the development of a PET tracer to image the expression of α5 β1 integrin receptors. An alkynyl precursor (PMt) was initially synthesized in six steps, and its radiolabeling was performed according to the azide-alkyne copper(II)-catalyzed Huisgen's cycloaddition by using 1-azido-2-[(18)F]fluoroethane ([(18)F]12). Different reaction conditions between PMt and [(18)F]12 were investigated, but all of them afforded [(18)F]FPMt in 15 min with similar radiochemical yields (80-83%, decay corrected). Overall, the final radiopharmaceutical ([(18)F]FPMt) was obtained after a synthesis time of 60-70 min in 42-44% decay-corrected radiochemical yield.

Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 μM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity.

Footnotes, March 2015, Vol. 40, no.1-3

Monthly newsletter of State Library

1.° Fratris Bernardi de Virduno, ordinis Minorum, liber super totam astrologiam. — 2.° Liber de compositione et practica instrumenti astronomici, quod dicitur Turketus. — 3.° Tractatus de almanach : authore anonymo. — 4.° Theorica planetarum : authore Gerardo Carmonensi. — 5.° Liber Thebit de motu octavae sphaerae. — 6.° Ejusdem liber de iis quae indigent expositione antequam legatur almagestum Ptolemaei. — 7.° Ejusdem liber de imaginatione sphaerae et circulorum ejus diversorum. — 8.° Ejusdem liber de quantitatibus stellarum et planetarum.

Colbertinus

1.° Picatricis, Hispani, astrologia, tribus libris. — 2.° Mauritii de Gregorio, Siculi Camaratensis, ordinis Fratrum Praedicatorum, in Prosperi Aldorisii gelotoscopiam commentarii. — 3.° Anonymus de piscibus. — 4.° Rolandi physionomia in sex libros divisa.

Tellerianus

fragmenta varia simul compacta hoc ordine : — 1.° Anonymi libellus de nativitatibus. — 2.° Excerptum è libro Petri de Alliaco, Cameracensis Episcopi, de imagine mundi. — 3.° Fragmentum registri cujusdam Procuratoris nomine Guaillardi. — 4.° Fragmentum Ciceronis de optimo genere Oratorum. — 5.° Fragmentum libri cui titulus : manipulus florum, è variis sanctorum Patrum locis collectus à Magistro Thoma de Hybernia, quondam Socio de Sorbona. — 6.° Catalogus operum quorum authores feruntur Dionysius, Augustinus, Ambrosius, Hieronymus, Gregorius, Bernardus, Hilarius, Isidorus, Chrysostomus, Rabanus, Prosper, Damascenus, Anselmus, Richardus et Hugo de Sancto Victore, Alanus, Cicero, Boëtius et Seneca : finis desideratur. — Hujusce codicis pars duodecimo, pars decimo quarto saeculo videtur exarata.

nuper comparatus

1.° Hilperici tractatus de arte calculatoria : praemittitur fragmentum de calendario. — 2.° Interrogationes et responsiones de computo. — 3.° Bedae liber de sex aetatibus mundi. — 4.° Adalbaldi, Episcopi Trajectensis, opusculum super illud Boëtii : O qui perpetua mundum ratione gubernas. — 5.° Anicii Manlii Severini Boëtii libri quinque de musica. — Hujusce codicis pars duodecimo, pars decimo tertio saeculo videtur exarata.

Colbertinus