The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor–water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.     

Spatial distribution and antifungal interactions of a Bacillus biological control agent on wheat surfaces

The proximity of a biological control agent and its associated anti-microbial metabolites to pathogens on plant surfaces can determine the outcome of disease control. In this study we investigated whether deficiencies in inoculum deposition and localization could explain the inability of the biological control agent Bacillus amyloliquefaciens strain TrigoCor to consistently control Fusarium head blight in the field, despite producing effective and consistent disease control in greenhouse settings. Using epifluorescent stereomicroscopy and confocal laser scanning microscopy, we visualized the coverage of wheat spike surfaces by Bacillus post-application in greenhouse and field environments, and determined that there are large unprotected areas on wheat spikes sprayed with commercial-scale field equipment, as compared to typical greenhouse applications. Additionally, we found that in conditions of low relative humidity, antifungal compounds produced by Bacillus were not able to diffuse across wheat surfaces in biologically relevant amounts, further suggesting that the inadequate coverage of wheat surfaces by Bacillus could be directly limiting disease control. Bacillus cells were easily rinsed off wheat surfaces within 8 h of application, indicating that rainfastness might be an additional limitation of biological control in field settings. Finally, we observed the inhibition of Fusarium graminearum spore germination by TrigoCor inoculum on wheat surfaces, confirming this as a mode of action for TrigoCor biocontrol. Future optimization efforts for biological control agents applied to above-ground plant parts should focus on enhancing the rainfastness, quantity, and spatial coverage of the inoculum on plant surfaces.     

Key factors controlling the size, biomass, and sprouting of Japanese alder swamp forest in Kushiro Mire, Hokkaido, Japan

The interrelation among size, biomass, and sprouting of alder trees was studied to extract the most important hydrochemistrical factors controlling the growth of alder forest in Kushiro Mire, northern Japan. The gradient was mostly explained by chemical variables such as pH, ash content, and P₂O₅, which showed strong positive correlation with each other, and secondarily by fluctuation of the water table (WL, i.e., water level range). These variables are more important than other hydrochemical ones, because neutral and turbid flood water replaces acidic mire water and conveys fine sediment with adsorbed phosphorus, which in turn could regulate the pH and amount of phosphorus. Also, the number of sprouts showed negative correlation mainly with tree size and redox potential (Eh), which suggested a flooded environment. Because of this, the size of alder was suppressed by hydrochemical variables; however, alder individuals producing new sprouts were maintained. We conclude that variation in size, biomass, and sprouting of alder was mainly controlled by acidity and phosphorus availability, and was significantly influenced by water fluctuation.     

Der Einfluß von Rapsextraktionsschrot und Methylthiourazil auf die Schilddrüsensekretionsrate von Hühnern nach kurzfristiger Fütterungsdauer

Three experiments were carried out with male broiler chickens reared from day‐ old to 6 weeks of age on semi‐purified diets containing 10% fresh (Expt. 1 and 3) or oxidized (Expt. 2) re‐esterified triglycerides with a fatty acid composition similar to that of soya bean oil containing increasing concentrations of either a mixture of d‐α‐, γ‐, δ‐tocopherylacetate (d‐tocopherols) of natural source or dl‐α‐ tocopheryl acetate (dl‐tocopherol). In Expt. 1 and 2 the mixture of d‐tocopherols consisted of 35.7% d‐α‐, 45.3% d‐γ‐ and 19.0% d‐δ‐, while in Expt. 3 the distribution was 25.3% d‐α‐, 28.1% d‐γ‐and 10.8% d‐γ‐ in 35.8% re‐ esterified triglycerides. The relative biopotency of d‐α‐: γ‐: δ‐tocopherol was anticipated to be 100: 25: 1, whereas that of dl‐a‐tocopherol was 74% relative to d‐ a‐tocopherol. The experiments demonstrate that the results obtained for the biological activity depend on the response parameters chosen. With respect to gain in weight, feed conversion, relative organ weight, packed cell volume (PCV), ELP (erythrocytelipidperoxidation), plasma activities of glutamate‐oxaloacetate‐transaminase (GOT), creatine kinase (CK) and glutathione peroxidase (GSH‐Px) and plasma Na⁺ concentration, the mixture of natural source tocopherols was identical to that of dl‐α‐tocopheryl acetate, although the concentration of a‐ tocopherol was only about one third of that of dl‐α‐tocopherol. Differences between natural source and synthetic tocopherols were expectedly observed with respect to plasma concentrations of α‐, γ‐, δ‐tocopherol. Differences between the two forms as to muscular dystrophy, in vitro haemolysis and potassium concentration in plasma were ambigous. It is suggested that the function of d‐α‐, γ‐, δ‐tocopherol in erythrocyte fragility and skeletal muscle structure should be compared to that of dl‐α‐tocopherol in future investigations.     

Wheat-yellow pumpkin composite flour: Physico-functional,rheological, antioxidant potential and quality properties of pan and flat bread

The impact of yellow pumpkin powder (YP) substitution (5, 10, and 15%) on wheat flour's physico-functional, pasting, gel texture, and dough rheology was studied. Moreover, the nutritional, organoleptic properties and bioactivity of the composite pan and pita bread were evaluated. An improved water holding capacity was noticed for the blended flour than for control. The pasting parameters were declined significantly (p < 0.05) with increasing YP. Composite flours presented a softer gel texture in the presence of YP. Reduced water absorption, increased dough development time, and lower stability for combined flour dough. The bread with YP depicted increased protein, fat, fiber, and mineral contents, while a reduced volume and specific volume were noticed for pan bread. YP incorporated 5% and did not compromise pan and pita bread's color and overall acceptability. Additionally, composite bread depicted higher total phenolics with enhanced antioxidant activities at the higher substitution of YP.     

Network environ analysis for socio-economic water system

Embodied water in a socio-economic system refers to the hidden water contained in products traded from one region or one sector to another and has been the center of concern for water management in recent years. However, most models developed for water system analysis ignore cycling and indirect flows, making it difficult to explain the effects of structure on these factors among sectors. Therefore, those models fail to examine the water utilization efficiency from an integral view. In this study, we investigate an embodied socio-economic water system using network analysis developed originally for ecological systems. In this manner, we identify structural and throughflow indicators, such as Finn Cycling Index, Indirect effects ratio, and aggradation, to show the efficiency of water utilization. The three indicators show different perspectives of the system's efficiency change over time, indicating that only the combination of these three indicators can provide a holistic portray about efficiency. Results showed that the structure influenced the cycling and indirect flows, and from a throughflow perspective, the system depends on large boundary inputs of fresh water. Furthermore, the values of Cycling Index and Indirect effect ratio are much lower than for natural food webs, implying that the policies that led to the structural change and reduction of boundary fresh water inputs do not lead to positive water utilization seen in natural systems. This study provides a novel perspective and methodology for assessing the structure and efficiency of water utilization system with a whole perspective.     

The Pressurized Porous Surface Model: An improved tool to study bacterial behavior under a wide range of environmentally relevant matric potentials

To study bacterial behavior under varying hydration conditions similar to surface soil, we have developed a system called the Pressurized Porous Surface Model (PPSM). Thin liquid films created by imposing a matric potential of − 0.4 MPa impact gene expression and colony development in Pseudomonas putida.