A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism:lessons from class B crystal structuress

The glucagon-like peptide 1 (GLP-1) receptor is a class B G protein-coupled receptor (GPCR) that is a key target for treatments for type II diabetes and obesity. This receptor, like other class B GPCRs, displays biased agonism, though the physiologic significance of this is yet to be elucidated. Previous work has implicated R2.60190 , N3.43240 , Q7.49394 , and H6.52363 as key residues involved in peptide-mediated biased agonism, with R2.60190 , N3.43240 , and Q7.49394 predicted to form a polar interaction network. In this study, we used novel insight gained from recent crystal structures of the transmembrane domains of the glucagon and corticotropin releasing factor 1 (CRF1) receptors to develop improved models of the GLP-1 receptor that predict additional key molecular interactions with these amino acids. We have introduced E6.53364 A, N3.43240 Q, Q7.49493N, and N3.43240 Q/Q7.49 Q/Q7.49493N mutations to probe the role of predicted H-bonding and charge-charge interactions in driving cAMP, calcium, or extracellular signal-regulated kinase (ERK) signaling. A polar interaction between E6.53364 and R2.60190 was predicted to be important for GLP-1- and exendin-4-, but not oxyntomodulin-mediated cAMP formation and also ERK1/2 phosphorylation. In contrast, Q7.49394 , but not R2.60190 /E6.53364 was critical for calcium mobilization for all three peptides. Mutation of N3.43240 and Q7.49394 had differential effects on individual peptides, providing evidence for molecular differences in activation transition. Collectively, this work expands our understanding of peptide-mediated signaling from the GLP-1 receptor and the key role that the central polar network plays in these events.

Charles Perry and Nathaniel Reed in Mesa Verde Cave

Charles Perry and Nathaniel Reed in Mesa Verde cave, Arizona. Charles Edward Perry (Chuck), 1937-1999, was the founding president of Florida International University in Miami, Florida. He grew up in Logan County, West Virginia and graduated from Bowling Green State University. He married Betty Laird in 1961. In 1969, at the age of 32, Perry was the youngest president of any university in the nation. The name of the university reflects Perry’s desire for a title that would not limit the scope of the institution and would support his vision of having close ties to Latin America. Perry and a founding corps opened FIU to 5,667 students in 1972 with only one large building housing six different schools. Perry left the office of President of FIU in 1976 when the student body had grown to 10,000 students and the university had six buildings, offered 134 different degrees and was fully accredited. Charles Perry died on August 30, 1999 at his home in Rockwall, Texas. He is buried on the FIU campus in front of the Graham Center entrance. Reed, Nathaniel P. (Nathaniel Pryor), 1933- serves on the Board of the National Geographic Society, the Everglades Foundation where he is Vice Chairman, and the Hope Rural School for migrant children. He received a B.A. from Trinity College in Connecticut. He was an officer in the U.S. Air Force and was Assistant Secretary of the Interior for the U.S. Fish and Wildlife Service as well as the U.S. Parks Service. He has also served on the boards of the National Audubon Society, the Nature Conservancy, the National Parks and Conservation Association, and the American Rivers. He is a board member emeriti of the Natural Resources Defense Council and 1000 Friends of Florida. He served on various environmental organization and committees under seven different governors in the state of Florida including as Chairman of the Commission on Florida’s Environmental Future. In 1972 he received the Cornelius Amory Pugsley National Medal Award.

Avaliação do desempenho de argamassas à base de cimento Portland para rejuntamento de placas cerâmicas tipo II com adição de pó de borracha de pneus

In this work it is assessed the performance of Portland cement-based mortar to the grouting of type II ceramic plates with the addition of unusable tire rubber powder. It is presented a bibliographical review about the subject in which is done the theoretical and methodological foundation of the whole investigative process. The analyzed universe comprises a sample of mortar to the grouting of conventional ceramic plates type II (reference sample) and five more samples to the grouting of ceramic plates type II, which were made up of the addition of unusable tire rubber powder in the respective proportion (in mass) of 4%, 8%, 12%, 16% and 20%. These mortar samples were subject to the trials of determination of the consistency index (Brazilian Standard NBR 13276:2005), water retention ( Brazilian Standard NBR 14992 Attachment B:2003), permeability in 240 minutes (Brazilian Standard NBR 14992 Attachment G:2003), absorption of water by immersion (Brazilian Standard NBR 9781:2013), resistance to compression (Brazilian Standard NBR14992 Attachment D: 2003), resistance to traction in the flexion (Brazilian Standard NBR 13279:2005), resistance of traction adherence (Brazilian Standard NBR 14081 part 4:2012) and hardened mass density (Brazilian Standard NBR 13280: 2005). It has been found out from the analyzes of the results in the trial the following situation: the reference mortar used met the established requirements in the norms of specifications corresponding to only six from the eight parameters assessed in the research; the mortar with addition of 4,0% of tire rubber powder met the established requirements corresponding to only the resistance to compression and the resistance of adherence to traction. Thus, the other kinds of mortar with addition of 8,0 %, 12,0 %, 16,0 % and 20,0 % of tire rubber powder met the requirements of specifications corresponding to only the resistance to compression and the resistance of adherence to traction. This result concludes that the adding of tire rubber powder does not grant improvement to the mortar of type II grouting to the laying of ceramic plates.

Avaliação do desempenho de argamassas à base de cimento Portland para rejuntamento de placas cerâmicas tipo II com adição de pó de borracha de pneus

In this work it is assessed the performance of Portland cement-based mortar to the grouting of type II ceramic plates with the addition of unusable tire rubber powder. It is presented a bibliographical review about the subject in which is done the theoretical and methodological foundation of the whole investigative process. The analyzed universe comprises a sample of mortar to the grouting of conventional ceramic plates type II (reference sample) and five more samples to the grouting of ceramic plates type II, which were made up of the addition of unusable tire rubber powder in the respective proportion (in mass) of 4%, 8%, 12%, 16% and 20%. These mortar samples were subject to the trials of determination of the consistency index (Brazilian Standard NBR 13276:2005), water retention ( Brazilian Standard NBR 14992 Attachment B:2003), permeability in 240 minutes (Brazilian Standard NBR 14992 Attachment G:2003), absorption of water by immersion (Brazilian Standard NBR 9781:2013), resistance to compression (Brazilian Standard NBR14992 Attachment D: 2003), resistance to traction in the flexion (Brazilian Standard NBR 13279:2005), resistance of traction adherence (Brazilian Standard NBR 14081 part 4:2012) and hardened mass density (Brazilian Standard NBR 13280: 2005). It has been found out from the analyzes of the results in the trial the following situation: the reference mortar used met the established requirements in the norms of specifications corresponding to only six from the eight parameters assessed in the research; the mortar with addition of 4,0% of tire rubber powder met the established requirements corresponding to only the resistance to compression and the resistance of adherence to traction. Thus, the other kinds of mortar with addition of 8,0 %, 12,0 %, 16,0 % and 20,0 % of tire rubber powder met the requirements of specifications corresponding to only the resistance to compression and the resistance of adherence to traction. This result concludes that the adding of tire rubber powder does not grant improvement to the mortar of type II grouting to the laying of ceramic plates.

(Appendix B) Dinoflagellate cysts in Southeast Pacific Ocean surface sediments

orty-eight surface sediment samples from the southeast (SE) Pacific (25-53°S) are investigated for the determination of the spatial distribution of organic-walled dinoflagellate cysts along the western South American continental margin. Fifty-five different taxa are recorded and reflect oceanic or coastal assemblages. The oceanic assemblages are characterised by low cyst concentrations and the dominance of autotrophs, while the coastal assemblages generally contain a higher number of cysts, which are mainly produced by heterotrophic species. Highest cyst concentrations are observed in the active upwelling system offshore Concepción (35-37°S). Brigantedinium spp., Echinidinium aculeatum, Echinidinium granulatum/delicatum and cysts of Protoperidinium americanum dominate assemblages related to upwelling. Echinidinium aculeatum appears to be the best indicator for the presence of all year round active upwelling cells. Other protoperidinioid cysts may also occur in high relative abundances in coastal regions outside active upwelling systems, if the availability of nutrients, co-responsible for the presence/absence of their main food sources such as diatoms and other protists, is sufficient. The importance of nutrient availability as a determining environmental variable influencing cyst signals on a regional scale (SE Pacific) is demonstrated through statistical analyses of the data. Because of the importance of nutrients, uncertainties about the outcomes of quantitative sea-surface temperature (SST) reconstructions (Modern Analogue Technique) based on dinoflagellate cysts may arise, since no interaction between different hydrographical variables is considered in this approach. The combination of the SE Pacific surface sample dataset with other published cyst data from the Southern Hemisphere resulted in a database which includes 350 samples: the 'SH350 database'. This database is used to test the accuracy of the quantitative reconstructions by calculating and comparing the estimated versus observed values for each site. An attempt to perform quantitative SST reconstructions on the last 25 cal ka of site ODP1233 (41°S; 74°27'W) is made and again stresses the importance of other environmental variables such as nutrient availability in determining the dinoflagellate cyst assemblages.

Long-Acting b-Agonist in Combination or Separate Inhaler as Step-Up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids

Acknowledgments The authors thank Prof. Stanley Szefler for his comments on the paper and Lisa Law for help with editing

Formation of sub-7 nm feature size PS-b-P4VP block copolymer structures by solvent vapour process

The nanometer range structure produced by thin films of diblock copolymers makes them a great of interest as templates for the microelectronics industry. We investigated the effect of annealing solvents and/or mixture of the solvents in case of symmetric Poly (styrene-block-4vinylpyridine) (PS-b-P4VP) diblock copolymer to get the desired line patterns. In this paper, we used different molecular weights PS-b-P4VP to demonstrate the scalability of such high χ BCP system which requires precise fine-tuning of interfacial energies achieved by surface treatment and that improves the wetting property, ordering, and minimizes defect densities. Bare Silicon Substrates were also modified with polystyrene brush and ethylene glycol self-assembled monolayer in a simple quick reproducible way. Also, a novel and simple in situ hard mask technique was used to generate sub-7nm Iron oxide nanowires with a high aspect ratio on Silicon substrate, which can be used to develop silicon nanowires post pattern transfer.

IL-10-producing Regulatory B Cell Development in Human Autoimmune Disease

B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of costimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of “regulatory B cells” has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported with interleukin-10 (IL-10) being the most studied. IL-10-producing regulatory B cells predominantly localize within a rare CD1dhiCD5+ B cell subset in mice and the CD24hiCD27+ B cell subset in adult humans. This specific IL-10-producing subset of regulatory B cells have been named “B10 cells” to highlight that the regulatory function of these rare B cells is primarily mediated by IL-10, and to distinguish them from other regulatory B cell subsets that regulate immune responses through different mechanisms. B10 cells have been studies in a variety of animal models with autoimmune disease and clinical settings of human autoimmunity. There are many unsolved questions related to B10 cells including their surface phenotype, their origin and development in vivo, and their role in autoimmunity.

In Chapter 3 of this dissertation, the role of the B cell receptor (BCR) in B10 cell development is highlighted. First, the BCR repertoire of mouse peritoneal cavity B10 cells is examined by single cell sequencing; peritoneal cavity B10 cells have clonally diverse germline BCRs that are predominantly unmutated. Second, mouse B10 cells are shown to have higher frequencies of λ+ BCRs compared to non-B10 cells which may indicate the involvement of BCR light chain editing early in the process of B10 cell development in vivo. Third, human peripheral blood B10 cells are examined and are also found to express higher frequencies of λ chains compared to non-b10 cells. Therefore, B10 cell BCRs are clonally diverse and enriched for unmutated germline sequences and λ light chains.

In Chapter 4 of this dissertation, B10 cells are examined in the healthy developing human across the entire age range of infancy, childhood and adolescence, and in a large cohort of children with autoimmunity. The study of B10 cells in the developing human documents a massive transient expansion during middle childhood when up to 30% of blood B cells were competent to produce IL-10. The surface phenotype of pediatric B10 cells was variable and reflective of overall B cell development. B10 cells down-regulated CD4+ T cell interferon-gamma (IFN-γ) production through IL-10-dependent pathways and IFN-γ inhibited whereas interleukin-21 (IL-21) promoted B cell IL-10 competency in vitro. Children with autoimmunity had a contracted B10 cell compartment, along with increased IFN-γ and decreased IL-21 serum levels compared to age-matched healthy controls. The decreased B10 cell frequencies and numbers in children with autoimmunity may be partially explained by the differential regulation of B10 cell development by IFN-γ and IL-21 and alterations in serum cytokine levels. The age-related changes of the B10 cell compartment during normal human development provide new insights into immune tolerance mechanisms involved in inflammation and autoimmunity.

These studies collectively demonstrate that BCR signals are the most important early determinant of B10 cell development in vivo, that human B10 cells are not a surface phenotype defined developmental B cell subset but a functionally defined regulatory B cell subset that regulates CD4+ T IFN-γ production through IL-10-dependent pathways and that human B10 cell development can be regulated by soluble factors in vivo such as the cytokine milieu. The findings of these studies provide new insights into immune tolerance mechanisms involved in human autoimmunity and the potent effects of IL-21 on human B cell IL-10 competence in vitro open new horizons in the development of autologous B10 cell-based therapies as an approach to treat human autoimmune disease in the future.

Adesp. fr. 700 K.-Sn. y "Andrómeda" de Eurípides

adesp. fr. 700 Kn.-Sn. podría proceder de Andrómeda de Eurípides y no de una Níobe. Los siguientes elementos de los frs. (a) y (b) pueden responder a lo que se conoce de la tragedia de Eurípides: (a) la semejanza con una estatua; (b) la novia de Hades; (c) el silencio del personaje; (d) la colaboración con las Moiras; (e) el contraste entre la fortuna regia y la desgracia y el sufrimiento de los padres. No es, por tanto, necesario modificar el texto recibido para eliminar μάγους πάγας y la referencia a las trampas mágicas en el v. 5, que cuadra bien con Medusa y Perseo.

The silent statue theme: complex imitation and Neo-Latin poetry

This paper analyses how the topic of the silent statue is dealt with in Neo-Latin literature. The subject matter comes from the epigrams about Pythagoras of the Palatine Anthology. There are numerous Neo-Latin imitations of this topic that are complex as various sources are used at the same time. The authors focus on an active reading of the epigrams of their predecessors, applying the traditional motive to new subjects and adapting it to the religious theme.

Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance)

PURPOSE: Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581.

PATIENTS AND METHODS: C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables.

RESULTS: Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk.

CONCLUSION: ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.

Preliminary Notes on Two Seasons of Research at Oplontis B (2014-2015)

The complex known as Oplontis B lies in the shadow of Vesuvius, about 3 kilometers west of Pompeii and 300 meters from the well-known Villa A. Since its first excavation and reconstruction in the 1970s and 1980s, Oplontis B has languished in abandonment ―virtually unstudied. The Oplontis Project, led by John Clarke and Michael Thomas, began investigating the site in 2012 after completing its work on Villa A. The documentation of the complex is a primary task. In the past few years members of the Project team have cataloged the previously excavated materials, recording over 1200 wine amphorae as well as a variety of other artifacts. At the same time, Marcus Abbott has laser-scanned the building to produce a detailed plan of the site. The excavations have similar aims: to record the 79 CE level of the complex and to investigate its development. This paper discusses the preliminary results of the last two seasons of excavations and cataloging efforts which build on our previous work conducted in 2012 and 2013.

Protein encapsulation and release from PEO-b-polyphosphoester templated calcium carbonate particles

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