Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor

The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery

Independence in CLP Languages

Studying independence of goals has proven very useful in the context of logic programming. In particular, it has provided a formal basis for powerful automatic parallelization tools, since independence ensures that two goals may be evaluated in parallel while preserving correctness and eciency. We extend the concept of independence to constraint logic programs (CLP) and prove that it also ensures the correctness and eciency of the parallel evaluation of independent goals. Independence for CLP languages is more complex than for logic programming as search space preservation is necessary but no longer sucient for ensuring correctness and eciency. Two additional issues arise. The rst is that the cost of constraint solving may depend upon the order constraints are encountered. The second is the need to handle dynamic scheduling. We clarify these issues by proposing various types of search independence and constraint solver independence, and show how they can be combined to allow dierent optimizations, from parallelism to intelligent backtracking. Sucient conditions for independence which can be evaluated \a priori" at run-time are also proposed. Our study also yields new insights into independence in logic programming languages. In particular, we show that search space preservation is not only a sucient but also a necessary condition for ensuring correctness and eciency of parallel execution

Clinical intestinal transplantation: New perspectives and immunologic considerations

Background: Although tacrolimus-based immunosuppression has made intestinal transplantation feasible, the risk of the requisite chronic high- dose treatment has inhibited the widespread use of these procedures. We have examined our 1990-1997 experience to determine whether immunomodulatory strategies to improve outlook could be added to drug treatment. Study Design: Ninety-eight consecutive patients (59 children, 39 adults) with a panoply of indications received 104 allografts under tacrolimus-based immunosuppression: intestine only (n = 37); liver and intestine (n = 50); or multivisceral (n = 17). Of the last 42 patients, 20 received unmodified adjunct donor bone marrow cells; the other 22 were contemporaneous control patients. Results: With a mean followup of 32 ± 26 months (range, 1-86 months), 12 recipients (3 intestine only, 9 composite grafts) are alive with good nutrition beyond the 5-year milestone. Forty-seven (48%) of the total group survive bearing grafts that provide full (91%) or partial (9%) nutrition. Actuarial patient survival at 1 and 5 years (72% and 48%, respectively) was similar with isolated intestinal and composite graft recipients, but the loss rate of grafts from rejection was highest with intestine alone. The best results were in patients between 2 and 18 years of age (68% at 5 years). Adjunct bone marrow did not significantly affect the incidence of graft rejection, B-cell lymphoma, or the rate or severity of graft-versus-host disease. Conclusions: These results demonstrate that longterm rehabilitation similar to that with the other kinds of organ allografts is achievable with all three kinds of intestinal transplant procedures, that the morbidity and mortality is still too high for their widespread application, and that the liver is significantly but marginally protective of concomitantly engrafted intestine. Although none of the endpoints were markedly altered by donor leukocyte augmentation (and chimerism) with bone marrow, establishment of the safety of this adjunct procedure opens the way to further immune modulation strategies that can be added to the augmentation protocol

Dinâmica do potencial redox em condições de alagamento em amostras de latossolo amarelo, textura média do nordeste paraense.

Resumo: Os Latossolos Amarelos textura média é a classe de solo predominante no nordeste paraense aonde a atividade do cultivo da palma de óleo (dendezeiro) que é uma atividade tradicional e em expansão. Um dos desafios para a expansão da palmicultura é a elucidação da etiologia do agente causal da anomalia conhecida como amarelecimento fatal. Entre as hipóteses que estão sendo testada é estsão os distúrbios provocados na solução do solo devido a alteração do potencial redox em condições de alagamento e consequentemente redução do oxigênio no solo. O presente experimento teve como objetivo estudar a variação do potencial oxirredução em amostras de um Latossolo Amarelo, textura média, distrófico submetido a condições de alagamento por um período de 60 dias. Adicionalmente se testou o efeito da homogeneização da amostras na avaliação do potencial redox. As amostras de solo foram coletadas numa área de cultivo de palma de óleo no município de Moju - PA, com incidência de amarelecimento fatal. Estas amostras posteriormente foram alagadas por um período de 60 dias. Durante este período, o potencial redox foi medido semanalmente . Os resultados mostraram que o potencial redox se reduz com o tempo de alagamento, sendo limitado por deficiência de carbono. Não houve diferenças significativas nas leituras do potencial redox com e sem homogeneização das amostras.A adição de uma fonte adicional de carbono (glucose) levou o potencial a valores de – 350 mV, nestas condições e com baixo valor de pH típico destes solos predominam as formas reduzidas de Fe, Mn e N que podem causar distúrbios fisiológicos a palma de óleo e outros cultivos

Understanding State Preferences With Text As Data: Introducing the UN General Debate Corpus

Every year at the United Nations, member states deliver statements during the General Debate discussing major issues in world politics. These speeches provide invaluable information on governments’ perspectives and preferences on a wide range of issues, but have largely been overlooked in the study of international politics. This paper introduces a new dataset consisting of over 7,300 country statements from 1970-2014. We demonstrate how the UN General Debate Corpus (UNGDC) can be used to derive country positions on different policy dimensions using text analytic methods. The paper provides applications of these estimates, demonstrating the contribution the UNGDC can make to the study of international politics

Density matrix reconstruction from displaced photon number distributions

We consider state reconstruction from the measurement statistics of phase space observables generated by photon number states. The results are obtained by inverting certain infinite matrices. In particular, we obtain reconstruction formulas, each of which involves only a single phase space observable.Comment: 19 page

Seletividde de agrotóxicos aos parasitoides de ovos Trichogramma pretiosum E Telenomus remus.

Os parasitoides de ovos destacam-se por atacarem a fase de ovo das pragas, controlando-as antes de causarem danos às plantas. Entretanto, a aplicação de agrotóxicos ainda é indispensável para garantir a boa produtividade das culturas. Neste contexto, em programas de manejo integrado de pragas (MIP), é recomendável utilizar diversas táticas para reduzir os danos dos insetos-praga e, portanto, a associação do controle químico e biológico é viável com a utilização de produtos seletivos aos inimigos naturais. Assim, avaliou-se a seletividade de espiromesifeno, flubendiamida, espirotetramate + imidacloprido, clorpirifós, cletodim, clorimurom-etílico, éster metílico de óleo de soja e a mistura deste último com espirotetramate + imidacloprido sobre os adultos de Trichogramma pretiosum Riley (Hymenoptera: Trichogrammatidae) e Telenomus remus (Nixon) (Hymenoptera: Scelionidae) e pupas de T. pretiosum segundo as normas padronizadas da “International Organization for Biological Control” (IOBC) em laboratório. Entre os tratamentos testados (g. ia/ha), os inseticidas espiromesifeno (144), flubendiamida (12) e espirotetramate (30) + imidacloprido (90) foram seletivos as fases dos parasitoides avaliadas. O adjuvante éster metílico de óleo de soja (360) também foi seletivo, entretanto, quando misturado com o espirotetramate (30) + imidacloprido (90) apresentou uma redução no parasitismo 2 e 5 dias após o início dos ensaios com T. remus e T. pretiosum, respectivamente. Flubendiamida (33,6) também foi seletivo para adultos de T. remus e pupas de T. pretiosum, mas reduziu a taxa de parasitismo após o segundo dia do ensaio com adultos de T. pretiosum. Os herbicidas cletodim (108) e clorimurom-etílico (20) foram seletivos a adultos de T. remus mas tiveram maior impacto sobre T. pretiosum reduzindo o parasitismo desse agente de controle biológico que se mostrou mais sensível a esses produtos. O inseticida clorpirifós (480) foi nocivo a todas as fases dos parasitoides avaliadas. Em geral, ocorreram diferenças na seletividade dos agrotóxicos avaliados aos inimigos naturais, além de diferenças na sensibilidade dos mesmos em relação aos produtos e doses testados. Portanto, em programas de MIP devem ser priorizados os agrotóxicos seletivos ao maior número de agentes de controle biológico.SICONBIOL 2011

Cytomegalovirus infection after intestinal transplantation in children

Sixteen episodes of cytomegalovirus (CMV) disease occurred in 10 of 41 children undergoing intestinal transplantation from 1990 to 1995. Stratification of CMV disease by donor (D)/recipient (R) serological status was as follows: 3 of 8, D+/R-; 3 of 9, D+/R+; 4 of 9, D-/R+; and 0 of 15, D- /R-. Treatment resulted in resolution of CMV disease in 93.3% of episodes. No deaths attributable to CMV disease occurred in this series. CMV in D+/R- children resulted in more extensive and persistent disease. However, patient and graft survival rates were similar in the different D/R subgroups and between children with and without CMV disease. Cumulative dose of steroid boluses (relative risk [RR], 1.59; 95% confidence interval [CI], 1.14-2.21) and history of steroid recycles (RR, 2.72; 95% CI, 1.21-6.13) were associated with CMV disease. These results suggest that although CMV-associated morbidity in pediatric intestinal transplant recipients was substantial, it was not associated with an increased rate of mortality or graft loss, even among high-risk D+/R- patients