Renewable beta-elemene based cyclic carbonates for the preparation of oligo(hydroxyurethane)s

Conversion of β-elemene into new β-elemene dicarbonates through epoxidation and halide salt-catalyzed CO2 cycloaddition reactions is reported. Step-growth polyaddition of this dicarbonate to five different, commercial diamines was investigated under neat conditions at 150 °C yielding non-isocyanate-based low molecular weight oligo(hydroxyurethane)s with 1.3≤Mn≤6.3 kDa and 1.3≤Ð≤2.1, and with glass transition temperatures ranging from −59 to 84 °C. The preparation of one selected polyhydroxyurethane material, obtained in the presence of Jeffamine® D-2010 was scaled-up to 43 g. The latter, when combined in a formulation using Irgacure® 2100 and Laromer® LR 9000 allowed the preparation of coatings that were analyzed with several techniques showing the potential of these biobased oligourethanes towards the preparation of commercially relevant materials

Slim LSTM networks: LSTM_6 and LSTM_C6

We have shown previously that our parameter-reduced variants of Long Short-Term Memory (LSTM) Recurrent Neural Networks (RNN) are comparable in performance to the standard LSTM RNN on the MNIST dataset. In this study, we show that this is also the case for two diverse benchmark datasets, namely, the review sentiment IMDB and the 20 Newsgroup datasets. Specifically, we focus on two of the simplest variants, namely LSTM_6 (i.e., standard LSTM with three constant fixed gates) and LSTM_C6 (i.e., LSTM_6 with further reduced cell body input block). We demonstrate that these two aggressively reduced-parameter variants are competitive with the standard LSTM when hyper-parameters, e.g., learning parameter, number of hidden units and gate constants are set properly. These architectures enable speeding up training computations and hence, these networks would be more suitable for online training and inference onto portable devices with relatively limited computational resources.Comment: 6 pages, 12 figures, 5 table

A comprehensive study on the role of the Yersinia pestis virulence markers in an animal model of pneumonic plague

We determined the role of Yersinia pestis virulence markers in an animal model of pneumonic plague. Eleven strains of Y. pestis were characterized using PCR assays to detect the presence of known virulence genes both encoded by the three plasmids as well as chromosomal markers. The virulence of all Y. pestis strains was compared in a mouse model for pneumonic plague. The presence of all known virulence genes correlated completely with virulence in the Balb/c mouse model. Strains which lacked HmsF initially exhibited visible signs of disease whereas all other strains (except wild-type strains) did not exhibit any disease signs. Forty-eight hours post-infection, mice which had received HmsF– strains regained body mass and were able to control infection; those infected with strains possessing a full complement of virulence genes suffered from fatal disease. The bacterial loads observed in the lung and other tissues reflected the observed clinical signs as did the cytokine changes measured in these animals. We can conclude that all known virulence genes are required for the establishment of pneumonic plague in mammalian animal models, the role of HmsF being of particular importance in disease progression

The Adjuvanticity of an O. volvulus-Derived rOv-ASP-1 Protein in Mice Using Sequential Vaccinations and in Non-Human Primates

Adjuvants potentiate antigen-specific protective immune responses and can be key elements promoting vaccine effectiveness. We previously reported that the Onchocerca volvulus recombinant protein rOv-ASP-1 can induce activation and maturation of naïve human DCs and therefore could be used as an innate adjuvant to promote balanced Th1 and Th2 responses to bystander vaccine antigens in mice. With a few vaccine antigens, it also promoted a Th1-biased response based on pronounced induction of Th1-associated IgG2a and IgG2b antibody responses and the upregulated production of Th1 cytokines, including IL-2, IFN-γ, TNF-α and IL-6. However, because it is a protein, the rOv-ASP-1 adjuvant may also induce anti-self-antibodies. Therefore, it was important to verify that the host responses to self will not affect the adjuvanticity of rOv-ASP-1 when it is used in subsequent vaccinations with the same or different vaccine antigens. In this study, we have established rOv-ASP-1's adjuvanticity in mice during the course of two sequential vaccinations using two vaccine model systems: the receptor-binding domain (RBD) of SARS-CoV spike protein and a commercial influenza virus hemagglutinin (HA) vaccine comprised of three virus strains. Moreover, the adjuvanticity of rOv-ASP-1 was retained with an efficacy similar to that obtained when it was used for a first vaccination, even though a high level of anti-rOv-ASP-1 antibodies was present in the sera of mice before the administration of the second vaccine. To further demonstrate its utility as an adjuvant for human use, we also immunized non-human primates (NHPs) with RBD plus rOv-ASP-1 and showed that rOv-ASP-1 could induce high titres of functional and protective anti-RBD antibody responses in NHPs. Notably, the rOv-ASP-1 adjuvant did not induce high titer antibodies against self in NHPs. Thus, the present study provided a sound scientific foundation for future strategies in the development of this novel protein adjuvant

Effects and acceptability of implementing improved cookstoves and heaters to reduce household air pollution: a FRESH AIR study

The objective was to evaluate the effectiveness and acceptability of locally tailored implementation of improved cookstoves/heaters in low- and middle-income countries. This interventional implementation study among 649 adults and children living in rural communities in Uganda, Vietnam and Kyrgyzstan, was performed after situational analyses and awareness programmes. Outcomes included household air pollution (PM2.5 and CO), self-reported respiratory symptoms (with CCQ and MRC-breathlessness scale), chest infections, school absence and intervention acceptability. Measurements were conducted at baseline, 2 and 6-12 months after implementing improved cookstoves/heaters. Mean PM2.5 values decrease by 31% (to 95.1 µg/m3) in Uganda (95%CI 71.5-126.6), by 32% (to 31.1 µg/m3) in Vietnam (95%CI 24.5-39.5) and by 65% (to 32.4 µg/m3) in Kyrgyzstan (95%CI 25.7-40.8), but all remain above the WHO guidelines. CO-levels remain below the WHO guidelines. After intervention, symptoms and infections diminish significantly in Uganda and Kyrgyzstan, and to a smaller extent in Vietnam. Quantitative assessment indicates high acceptance of the new cookstoves/heaters. In conclusion, locally tailored implementation of improved cookstoves/heaters is acceptable and has considerable effects on respiratory symptoms and indoor pollution, yet mean PM2.5 levels remain above WHO recommendations.European Union’s Horizon 2020 programme under grant agreement no. 680997, TRIAL ID NTR5759, http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=23332. The devices, measuring the personal HAP, were funded by Netherlands Enterprise Agency (RVO

Helminth Genomics: The Implications for Human Health

More than two billion people (one-third of humanity) are infected with parasitic roundworms or flatworms, collectively known as helminth parasites. These infections cause diseases that are responsible for enormous levels of morbidity and mortality, delays in the physical development of children, loss of productivity among the workforce, and maintenance of poverty. Genomes of the major helminth species that affect humans, and many others of agricultural and veterinary significance, are now the subject of intensive genome sequencing and annotation. Draft genome sequences of the filarial worm Brugia malayi and two of the human schistosomes, Schistosoma japonicum and S. mansoni, are now available, among others. These genome data will provide the basis for a comprehensive understanding of the molecular mechanisms involved in helminth nutrition and metabolism, host-dependent development and maturation, immune evasion, and evolution. They are likely also to predict new potential vaccine candidates and drug targets. In this review, we present an overview of these efforts and emphasize the potential impact and importance of these new findings

A Helminth Immunomodulator Exploits Host Signaling Events to Regulate Cytokine Production in Macrophages

Parasitic worms alter their host's immune system to diminish the inflammatory responses directed against them, using very efficient immunomodulating molecules. We have previously shown that the helminth immunomodulator cystatin (AvCystatin) profoundly reduces the progression of inflammatory diseases via modulation of macrophages. Here we elucidate the signaling events in macrophages triggered by AvCystatin. Labeled AvCystatin was predominantly taken up by macrophages and subsequently induced the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38. IL-10 expression induced by AvCystatin in macrophages was tyrosine kinase sensitive and dependent on activation of both MAP kinases, in clear contrast to expression of IL-12/23p40. In addition, phosphorylation of the transcription factors CREB and STAT3 was induced by AvCystatin and regulated by phospho-ERK. Chemical inhibition of phosphoinositide 3-kinase (PI3K) reduced AvCystatin-induced cytokine release; however, AKT, the downstream target of PI3K, was not activated following AvCystatin exposure. To characterize signaling elements involved in alteration of the macrophage phenotype we applied mathematical modeling. Experimental testing of the in silico generated hypotheses identified dual specificity phosphatase (DUSP) 1 and 2, as regulators in AvCystatin triggered macrophages in vitro and in vivo. In particular, DUSP1 was subsequently found to be responsible for regulation of ERK- and p38-phosphorylation and controlled the IL-10 expression in macrophages by AvCystatin. Thus, we show that AvCystatin exploits activation and deactivation pathways of MAP kinases to induce regulatory macrophages. This study provides insights into molecular mechanisms of macrophage manipulation by parasites and highlights the utility of mathematical modeling for the elucidation of regulatory circuits of immune cells

Association of the Gene Polymorphisms IFN-γ +874, IL-13 −1055 and IL-4 −590 with Patterns of Reinfection with Schistosoma mansoni

Approximately 200 million people have schistosomiasis in parts of Africa, South America, the Middle East, the Caribbean and Asia. Several studies of multiple treatments and reinfections indicate that some people develop resistance to reinfection. Of all the immunologic findings associated with such studies, the most consistent observation is that resistance (usually defined as lower levels of infection upon reinfection) correlates with high IgE and low IgG4 antibodies against schistosome antigens. Our studies test whether single nucleotide polymorphisms residing in the gene or promoter regions of cytokines pivotal in controlling production of these antibody isotypes are different amongst those that develop resistance to reinfection as opposed to those that do not. Through genotyping of these polymorphisms in a cohort of occupationally exposed car washers, we found that men with certain genotypic patterns of polymorphisms in IL-4, IFN-γ, and IL-13 were significantly more likely to be resistant to reinfection than those with different patterns. These data provide initial insights into the potential genetic foundation of propensities of people to develop resistance to reinfection by schistosomes, and offer a basis for further molecular studies of how these polymorphisms might work at the transcriptional and gene product level in cells stimulated by schistosome antigens