Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation

Different c-Jun N-terminal kinases (JNKs) are activated by a plethora of signals and phosphorylate substrates such as c-Jun, which is required for efficient cell cycle progression. Although JNK1 and JNK2 were shown to differentially regulate fibroblast proliferation, the underlying mechanistic basis remains unclear. We found that Jnk2-/- fibroblasts exit G1 and enter S phase earlier than wild-type counterparts, while Jnk1-/- cells show the inverse phenotype. Moreover, Jnk2-/- erythroblasts also exhibit a proliferative advantage. JNK2 deficiency results in elevated c-Jun phosphorylation and stability, whereas the absence of JNK1 reduces c-Jun phosphorylation and stability. Re-expression of JNK2 in Jnk2-/- cells reverses the JNK2 null phenotype, whereas ectopic expression of JNK1 augments it. JNK2 is preferentially bound to c-Jun in unstimulated cells, thereby contributing to c-Jun degradation. In contrast, JNK1 becomes the major c-Jun interacting kinase after cell stimulation. These data provide mechanistic insights into the distinct roles of different JNK isoforms.     

The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage

We previously determined that Notch2, and not Notch1, was required for forming proximal nephron segments. The dominance of Notch2 may be conserved in humans, since Notch2 mutations occur in Alagille syndrome (ALGS) 2 patients, which includes renal complications. To test whether mutations in Notch1 could increase the severity of renal complications in ALGS, we inactivated conditional Notch1 and Notch2 alleles in mice using a Six2-GFP::Cre. This BAC transgene is expressed mosaically in renal epithelial progenitors but uniformly in cells exiting the progenitor pool to undergo mesenchymal-to-epithelial transition. Although delaying Notch2 inactivation had a marginal effect on nephron numbers, it created a sensitized background in which the inactivation of Notch1 severely compromised nephron formation, function, and survival. These and additional observations indicate that Notch1 in concert with Notch2 contributes to the morphogenesis of renal vesicles into S-shaped bodies in a RBP-J-dependent manner. A significant implication is that elevating Notch1 activity could improve renal functions in ALGS2 patients. As proof of principle, we determined that conditional inactivation of Mint, an inhibitor of Notch-RBP-J interaction, resulted in a moderate rescue of Notch2 null kidneys, implying that temporal blockage of Notch signaling inhibitors downstream of receptor activation may have therapeutic benefits for ALGS patients.     

Atomic resolution crystal structures, EXAFS, and quantum chemical studies of rusticyanin and its two mutants provide insight into its unusual properties

Rusticyanin from the extremophile Thiobacillus ferrooxidans is a blue copper protein with unusually high redox potential and acid stability. We present the crystal structures of native rusticyanin and of its Cu site mutant His143Met at 1.27 and 1.10 A, respectively. The very high resolution of these structures allows a direct comparison with EXAFS data and with quantum chemical models of the oxidized and reduced forms of the proteins, based upon both isolated and embedded clusters and density functional theory (DFT) methods. We further predict the structure of the Cu(II) form of the His143Met mutant which has been experimentally inaccessible due to its very high redox potential. We also present metrical EXAFS data and quantum chemical calculations for the oxidized and reduced states of the Met148Gln mutant, this protein having the lowest redox potential of all currently characterized mutants of rusticyanin. These data offer new insights into the structural factors which affect the redox potential in this important class of proteins. Calculations successfully predict the structure and the order of redox potentials for the three proteins. The calculated redox potential of H143M ( approximately 400 mV greater than native rusticyanin) is consistent with the failure of readily available chemical oxidants to restore a Cu(II) species of this mutant. The structural and energetic effects of mutating the equatorial cysteine to serine, yet to be studied experimentally, are predicted to be considerable by our calculations.     

Physico-Mechanical Properties of Chemically Treated Bacterial (Acetobacter xylinum) Cellulose Membrane

Bacterial cellulose obtained through fermentation by the Acetobacter xylinum is of superior functional quality in comparison to plant cellulose. Various alkali treatment methods were used to process bio-chemically complex pellicle into a clean cellulose membrane/sheet. The effect of potassium hydroxide, sodium carbonate and potassium carbonate was found to be milder on the final cellulose product in contrast to the widely used sodium hydroxide treatment. These novel treatment methods also caused improvement in the tensile strength of the membranes in comparison to sodium hydroxide. The overall quality of the 0.1 M sodium carbonate- and potassium carbonate-treated cellulose was superior, as the membranes displayed maximum tensile strength and elongation next to the native membrane. The low tensile strength of sodium hydroxide-treated membrane is attributed to its higher swelling characteristics in alkali. Further, the low swelling property of sodium carbonate- and potassium carbonate-treated membranes resulted in their high oxygen transmission rates (low oxygen barrier). Hunter lab colour parameters were determined to assess the effect of different alkali treatments on the colour characteristics of the membranes. Further, based on the high mechanical strength and comparatively low oxygen transmission rates, the processed cellulose membranes may find application as a bio- packaging material for controlled atmosphere packaging, where hydrophilic membranes with high oxygen barrier and water vapour permeation are desirable.     

Associations of ATR and CHEK1 Single Nucleotide Polymorphisms with Breast Cancer

DNA damage and replication checkpoints mediated by the ATR-CHEK1 pathway are key to the maintenance of genome stability, and both ATR and CHEK1 have been proposed as potential breast cancer susceptibility genes. Many novel variants recently identified by the large resequencing projects have not yet been thoroughly tested in genome-wide association studies for breast cancer susceptibility. We therefore used a tagging SNP (tagSNP) approach based on recent SNP data available from the 1000 genomes projects, to investigate the roles of ATR and CHEK1 in breast cancer risk and survival. ATR and CHEK1 tagSNPs were genotyped in the Sheffield Breast Cancer Study (SBCS; 1011 cases and 1024 controls) using Illumina GoldenGate assays. Untyped SNPs were imputed using IMPUTE2, and associations between genotype and breast cancer risk and survival were evaluated using logistic and Cox proportional hazard regression models respectively on a per allele basis. Significant associations were further examined in a meta-analysis of published data or confirmed in the Utah Breast Cancer Study (UBCS). The most significant associations for breast cancer risk in SBCS came from rs6805118 in ATR (p=7.6x10^-5) and rs2155388 in CHEK1 (p=3.1x10^-6), but neither remained significant after meta-analysis with other studies. However, meta-analysis of published data revealed a weak association between the ATR SNP rs1802904 (minor allele frequency is 12%) and breast cancer risk, with a summary odds ratio (confidence interval) of 0.90 (0.83-0.98) [p=0.0185] for the minor allele. Further replication of this SNP in larger studies is warranted since it is located in the target region of 2 microRNAs. No evidence of any survival effects of ATR or CHEK1 SNPs were identified. We conclude that common alleles of ATR and CHEK1 are not implicated in breast cancer risk or survival, but we cannot exclude effects of rare alleles and of common alleles with very small effect sizes.     

Global simulation of bioenergy crop productivity: analytical framework and case study for switchgrass

A global energy crop productivity model that provides geospatially explicit quantitative details on biomass potential and factors affecting sustainability would be useful, but does not exist now. This study describes a modeling platform capable of meeting many challenges associated with global‐scale agro‐ecosystem modeling. We designed an analytical framework for bioenergy crops consisting of six major components: (i) standardized natural resources datasets, (ii) global field‐trial data and crop management practices, (iii) simulation units and management scenarios, (iv) model calibration and validation, (v) high‐performance computing (HPC) simulation, and (vi) simulation output processing and analysis. The HPC‐Environmental Policy Integrated Climate (HPC‐EPIC) model simulated a perennial bioenergy crop, switchgrass (Panicum virgatum L.), estimating feedstock production potentials and effects across the globe. This modeling platform can assess soil C sequestration, net greenhouse gas (GHG) emissions, nonpoint source pollution (e.g., nutrient and pesticide loss), and energy exchange with the atmosphere. It can be expanded to include additional bioenergy crops (e.g., miscanthus, energy cane, and agave) and food crops under different management scenarios. The platform and switchgrass field‐trial dataset are available to support global analysis of biomass feedstock production potential and corresponding metrics of sustainability.     

Plant growth regulator triggered metabolomic profile leading to increased lipid accumulation in an edible marine microalga

Journal of Applied Phycology - Omega-3 fatty acids containing microalgae are considered a promising feedstock for food and nutraceutical applications. To meet the commercial and nutritional demands...     

Correction to: Smart controlled environment agriculture methods: a holistic review

Reviews in Environmental Science and Bio/Technology -