Design and synthesis of tetrahydropyridopyrimidine based Toll-Like Receptor (TLR) 7/8 dual agonists

In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure–activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant.     

A quality improvement program to improve nutritional status of children with Cystic Fibrosis aged 2-12 years old over a 3 year period at CF center Roscoff,Brittany

Background

The Cystic Fibrosis (CF) center in Roscoff (Brittany) has been involved in therapeutic education programs (TEP) since 2006 and took part in the pilot phase of the French quality improvement program (QIP) since 2011. The aim was to improve the nutritional status of children with cystic fibrosis aged 2-12 years old in order to optimize their health status as they enter adolescence.

Methods

A multidisciplinary quality team was created in order to select and address a specific health problem among our pediatric population. Following analysis of yearly indicators for our CF center, our team chose to improve quality of care concerning nutritional status of children aged 2-12 years old. Factors influencing efficacy were studied, tools were developed to implement a new nutritional program, results were analyzed on a real-time basis.

Results

Over the 3 year period, all patients from 2 years of age, were monitored with the new follow-up program (2012: N =?34; 2014: N =?44). Each patient was followed up at every clinic visit, their BMI z-score was calculated to decide their nutritional risk and personalize their follow-up program consequently. Between 1/1/2012 and 31/12/2014, the mean BMI z-score of the open cohort improved from ?0.49 to ?0.22.

Conclusions

Since 2014, focus on nutrition using the newly-adapted program has become routine practice at each follow-up visit. Patients and parents expressed a high level of satisfaction (75% very satisfied). The follow-up program aimed at improving nutritional status for children aged 2-12 years old was successfully implemented and integrated into routine practice; it was therefore extended to all children with CF (1 month - 18 years) in our center. The relationship among professional and patients and parents was strengthened.

     

The seed lectins of black locust (robinia pseudoacacia) are encoded by two genes which differ from the bark lectin genes

Two lectins were isolated from Robinia pseudoacacia (black locust) seeds using affinity chromatography on fetuin-agarose, and ion exchange chromatography on a Neobar CS column. The first lectin, R. pseudoacacia seed agglutinin I, referred to as RPsAI, is a homotetramer of four 34 kDa subunits whereas the second lectin, referred to as RPsAII, is composed of four 29 kDa polypeptides. cDNA clones encoding the polypeptides of RPsAI and RPsAII were isolated and their sequences were determined. Both polypeptides are translated from mRNAs of ca. 1.2 kb encoding a precursor carrying a signal peptide. Alignment of the deduced amino acid sequences of the different clones indicates that the 34 and 29 kDa seed lectin polypeptides show 95% sequence identity. In spite of this striking homology, the 29 kDa polypeptide has only one putative glycosylation site whereas the 34 kDa subunit has four of these sites. Carbohydrate analysis revealed that the 34 kDa possesses three carbohydrate chains whereas the 29 kDa polypeptide is only partially glycosylated at one site. A comparison of the deduced amino acid sequences of the two seed and three bark lectin polypeptides demonstrated unambiguously that they are encoded by different genes. This implies that five different genes are involved in the control of the expression of the lectins in black locust.Abbreviations LECRPAs cDNA clone encoding Robinia pseudoacacia seed lectin - LoLI Lathyrus ochrus isolectin I - PsA Pisum sativum agglutinin - RPbAI Robinia pseudoacacia bark agglutinin I - RPbAII Robinia pseudoacacia bark agglutinin II - RPsAI Robinia pseudoacacia seed agglutinin I - RPsAII Robinia pseudoacacia seed agglutinin II     

Antibody Persistence and Booster Responses to Split-Virion H5N1 Avian Influenza Vaccine in Young and Elderly Adults

Avian influenza continues to circulate and remains a global health threat not least because of the associated high mortality. In this study antibody persistence, booster vaccine response and cross-clade immune response between two influenza A(H5N1) vaccines were compared. Participants aged over 18-years who had previously been immunized with a clade 1, A/Vietnam vaccine were re-immunized at 6-months with 7.5 μg of the homologous strain or at 22-months with a clade 2, alum-adjuvanted, A/Indonesia vaccine. Blood sampled at 6, 15 and 22-months after the primary course was used to assess antibody persistence. Antibody concentrations 6-months after primary immunisation with either A/Vietnam vaccine 30 μg alum-adjuvanted vaccine or 7.5 μg dose vaccine were lower than 21-days after the primary course and waned further with time. Re-immunization with the clade 2, 30 μg alum-adjuvanted vaccine confirmed cross-clade reactogenicity. Antibody cross-reactivity between A(H5N1) clades suggests that in principle a prime-boost vaccination strategy may provide both early protection at the start of a pandemic and improved antibody responses to specific vaccination once available.Trial Registration: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00415129","term_id":"NCT00415129"}}NCT00415129     

EXISTENCE OF A SPERMATOGONIAL CHALONE IN THE RAT TESTIS

Adult rats with normal or X-irradiated testes were used in an experiment to test the possible existence of a chalone in the testis. On the 11th day following irradiation, i.e. as the type A spermatogonia proliferated actively to restore the partially destroyed spermatogonial population, the animals with irradiated testes were subdivided into three groups. Rats of the first group were injected intraperitoneally with a saline extract of normal adult rat testes. Animals of the second group were injected with an equal amount of physiological saline while the rats of the third group received equivalent injections of a saline liver extract. Two additional groups of rats with non-irradiated testes, injected with the testicular extract or saline solution, served as controls. Following the last injection all animals were injected with ³H-thymidine and sacrificed. From each animal one testis was used to determine the specific radioactivity of its DNA, the other testis was processed for radioautography. The testicular extract produced a significant decrease in uptake of radioactivity by the irradiated testes. There was no difference in the radioactivity uptake by the testes of non-irradiated rats. Correspondingly the labeling index of type A spermatogonia was significantly lower in animals of the first group than in the other two groups of animals with irradiated testes. However, there was no difference in the labeling indices of Intermediate and type B spermatogonia or of preleptotene spermatocytes in the animals receiving the extracts or the saline solution. In animals with non-irradiated testes there was no difference in the labeling indices of type A or other types of spermatogonia or of spermatocytes. These data were taken to indicate that a saline extract of normal adult testes contains a substance that can inhibit specifically the proliferation of type A spermatogonia during the repair phase of the spermatogonial population following irradiation. This substance was tentatively considered as a spermatogonial chalone.     

Aeromonas species in stabilization ponds in the arid region of Marrakesh,Morocco, and relation to fecal-pollution and climatic factors

During the period 12 July 1985 to 23 December 1987, water samples were collected in two-week intervals for estimates ofAeromonas species in a waste treatment system located in the arid region of Marrakech, Morocco. Fecal coliforms, temperature, and chemical oxygen demand were measured simultaneously withAeromonas species densities. Statistical methods were utilized to analyze the significance of average differences and temporal patterns ofAeromonas species numbers. Removal ofAeromonas in the whole system did not exceed 1.14 log.Aeromonas densities showed significantly higher resistance to the treatment process when compared with fecal coliforms; however, abundance of the two groups presented a similar seasonal change. The highest numbers occurred during the cold months, while the lowest appeared in the warm months. Statistical time-series analyses of the densities data showed the seasonal and cyclic distribution ofAeromonas in this treatment plant. These temporal changes were simultaneously observed in all the stations investigated and were negatively correlated with water temperature values. Aeromonas populations were dominated byA. caviae andA. hydrophila in the inlet samples. These two species were rapidly eliminated in the treatment plant. The temporal distribution ofA. caviae was similar to the change in densities ofAeromonas and fecal coliforms. The seasonal fluctuations of abundance ofAeromonas were probably related to this species, which dominated in the winter samples but dropped during the summer. Meanwhile,A. sobria dominated all the final effluent samples. This greater survival ofA. sobria and its known pathogenicity may limit the re-use of treated water for irrigation of fodder plants.     

Dual coupling of the cloned 5-HT1A receptor to both adenylyl cyclase and phospholipase C is mediated via the same Gi protein.

The coloned 5-HT_1A receptor, stably expressed in HeLa cells, has been shown to mediate the effects of 5-hydroxytryptamine (5-HT) to inhibit cAMP formation and to stimulate the hydrolysis of phosphatidylinositol. Both responses were found to be pertussis toxin sensitive. We have examined these two responses in membranes derived from these cells and show that the 5-HT_1A receptor can directly regulate the activity of adenylyl cyclase and phospholipase C in response to agonist. In order to examine whether the same or distinct guanine nucleotide-binding regulatory protein(s) (G protein) are involved in these two signal transduction pathways, we used anti-peptide antibodies recognizing the -subunits of G_i1, G_i2, G_i3 as specific tools, since these pertussis toxin substrates are expressed in HeLa cells. These antibodies have previously been shown to prevent receptor-G protein coupling by binding to the regions of G proteins which are putatively involved in interaction with receptors. Our results indicate that the G_i proteins, but preferentially G₃, mediate the effects of 5-HT both to inhibit adenylyl cyclase and to stimulate phospholipase C. These findings demonstrate that the same receptor interacting with the same C protein can regulate several distinct effector molecules.