Use of textile waste water along with liquid NPK fertilizer for production of wheat on saline sodic soils

A field experiment in collaboration with a private textile industry (Noor Fatima Fabrics Private (Ltd.), Faisalabad) was conducted to evaluate the effect of disposed water from bleaching unit, printing unit and end drain for improving growth and yield of wheat under saline sodic soil. Textile waste water along with canal water (control) was applied with and without liquid NPK fertilizer. The application of liquid NPK fertilizer with end drain waste water increased plant height, spike length, flag leaf length, root length, number of tillers (m^?2), number of fertile tillers (m^?2), 1000 grain weight, grain yield, straw yield and biological yield up to 21, 20, 20, 44, 17, 20, 14, 44, 40 and 41%, respectively compared to canal water (control). Similarly, the NPK uptake in grain was increased up to 15, 30 and 28%, respectively by liquid fertilizer treated end drain water as compare to canal water with liquid fertilizer. Moreover, concentration of different heavy metals particularly Cu, Cr, Pb and Cd was decreased in grains by application of waste water along with liquid NPK. The result may imply that waste water application along with liquid-NPK could be a novel approach for improving growth and yield of wheat in saline sodic soils.     

The Dynamics of Conjunctive and Disjunctive Boolean Network Models

For many biological networks, the topology of the network constrains its dynamics. In particular, feedback loops play a crucial role. The results in this paper quantify the constraints that (unsigned) feedback loops exert on the dynamics of a class of discrete models for gene regulatory networks. Conjunctive (resp. disjunctive) Boolean networks, obtained by using only the AND (resp. OR) operator, comprise a subclass of networks that consist of canalyzing functions, used to describe many published gene regulation mechanisms. For the study of feedback loops, it is common to decompose the wiring diagram into linked components each of which is strongly connected. It is shown that for conjunctive Boolean networks with strongly connected wiring diagram, the feedback loop structure completely determines the long-term dynamics of the network. A formula is established for the precise number of limit cycles of a given length, and it is determined which limit cycle lengths can appear. For general wiring diagrams, the situation is much more complicated, as feedback loops in one strongly connected component can influence the feedback loops in other components. This paper provides a sharp lower bound and an upper bound on the number of limit cycles of a given length, in terms of properties of the partially ordered set of strongly connected components.     

Characterization of Dahl salt-sensitive rats with genetic disruption of the A2B adenosine receptor gene: implications for A2B adenosine receptor signaling during hypertension

The A_2B adenosine receptor (AR) has emerged as a unique member of the AR family with contrasting roles during acute and chronic disease states. We utilized zinc-finger nuclease technology to create A_2BAR gene (Adora2b)-disrupted rats on the Dahl salt-sensitive (SS) genetic background. This strategy yielded a rat strain (SS-Adora2b mutant rats) with a 162-base pair in-frame deletion of Adora2b that included the start codon. Disruption of A_2BAR function in SS-Adora2b mutant rats was confirmed by loss of agonist (BAY 60-6583 or NECA)-induced cAMP accumulation and loss of interleukin-6 release from isolated fibroblasts. In addition, BAY 60-6583 produced a dose-dependent increase in glucose mobilization that was absent in SS-Adora2b mutants. Upon initial characterization, SS-Adora2b mutant rats were found to exhibit increased body weight, a transient delay in glucose clearance, and reduced proinflammatory cytokine production following challenge with lipopolysaccharide (LPS). In addition, blood pressure was elevated to a greater extent (∼15–20 mmHg) in SS-Adora2b mutants as they aged from 7 to 21 weeks. In contrast, hypertension augmented by Ang II infusion was attenuated in SS-Adora2b mutant rats. Despite differences in blood pressure, indices of renal and cardiac injury were similar in SS-Adora2b mutants during Ang II-augmented hypertension. We have successfully created and validated a new animal model that will be valuable for investigating the biology of the A_2BAR. Our data indicate varying roles for A_2BAR signaling in regulating blood pressure in SS rats, playing both anti- and prohypertensive roles depending on the pathogenic mechanisms that contribute to blood pressure elevation.     

Phosphorylation of the receptor for PTH and PTHrP is required for internalization and regulates receptor signaling.

We have previously shown that agonist-dependent phosphorylation of the PTH/PTHrP receptor occurs on its carboxyl-terminal tail. Using site-directed mutagenesis, phosphopeptide mapping, and direct sequencing of cyanogen bromide-cleaved fragments of phosphoreceptors, we report here that PTH-dependent phosphorylation occurs on the serine residues at positions 491, 492, 493, 495, 501, and 504, and that the serine residue at position 489 is required for phosphorylation. When these seven sites were mutated to alanine residues, the mutant receptor was no longer phosphorylated after PTH stimulation. The phosphorylation-deficient receptor, stably expressed in LLCPK-1 cells, was impaired in PTH-dependent internalization and showed an increased sensitivity to PTH stimulation; the EC(50) for PTH-stimulated cAMP accumulation was decreased by 7-fold. Furthermore, PTH stimulation of the phosphorylation-deficient PTH/PTHrP receptor caused a sustained elevation in intracellular cAMP levels. These data indicate that agonist-dependent phosphorylation of the PTH/PTHrP receptor plays an important role in receptor function.     

Animal biomass in a New Zealand forest compared with other parts of the world

Summary Data on mammalian, avian and invertebrate biomass in mixed broadleaf-podocarp forest of the Orongorongo Valley are summarised and compared with the biomass in other forests. Animal biomass totalled at least 504 kg/ha — more than twice that in several tropical forests but less than that reported from temperate deciduous forests of Europe. Earthworms (333 kg/ha) provided most animal biomass: arthropods at least 145 kg/ha, mammals (all introduced) 25 kg/ha, and birds 0.6 kg/ha. By world standards the biomass of mammals, and litter-dwelling and underground arthropods, is high and that of birds moderate. Introduced mammals have greatly altered the distribution of biomass in this forest, herbivores and predatory mammals gaining biomass at the expense of some native aboveground invertebrates and birds, several of which have been lost to this community.     

Reliable structural information for rational design of benzoxazole type potential cholesteryl ester transfer protein (CETP) inhibitors through multiple validated modeling techniques

Abstract

The drug design and discovery of lipid modulators is very demanding as no new molecule has entered into the market in the last 35 years. Cholesteryl ester transfer protein (CETP) is a promising target as lipid modulators. Inhibition of the CETP enzyme reduces the risk of cardiovascular events. The first CETP inhibitor torcetrapib and related drug candidates failed in the clinical trial due to the off-target effects leading to high toxicity. Thus, newer CETP inhibitors have now paramount importance to accelerate the drug discovery efforts in the field of cardiovascular disease (CVD). In the present study, 140 benzoxazole compounds were studied by using different chemometric techniques, for example, pharmacophore mapping, molecular docking, three-dimensional quantitative structure–activity relationship comparative molecular field analysis (3D-QSAR CoMFA), topomer CoMFA and Bayesian classification, in order to generate complete and reliable information regarding the structural requirements for the CETP inhibition. The best pharmacophore hypothesis was statistically significant (regression coefficient of 0.957 and a lower root mean square of 0.890). Molecular docking study revealed that cyano-substituted compounds form hydrogen bond with targeted macromolecule. The 3D-QSAR CoMFA model also produced a leave-one-out (LOO) cross-validated Q² of 0.527, an R² of 0.853 and an R²_Pred of 0.603. Similarly, two topomer CoMFA models were also statistically significant and reliable in terms of their Q², R² and R²_Pred values. The Bayesian classification study also provided the excellent ROC values of 0.919 and 0.939 for training and test sets, respectively. Overall, this study may help in the rational design of newer benzoxazole type compounds with higher CETP inhibition.

Communicated by Ramaswamy H. Sarma     

Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)–negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.