Climate change and broadacre livestock production across southern Australia. 1. Impacts of climate change on pasture and livestock productivity,and on sustainable levels of profitability

Broadacre livestock production is a major but highly diverse component of agriculture in Australia that will be significantly exposed to predicted changes in climate over coming decades. We used the GRAZPLAN simulation models to assess the impacts of climate change under the SRES A2 scenario across southern Australia. Climate change impacts were examined across space (25 representative locations) and time (1970–99, 2030, 2050 and 2070 climate) for each of five livestock enterprises. Climate projection uncertainty was considered by analysing projections from four global circulation models (GCMs). Livestock production scenarios were compared at their profit‐maximizing stocking rate, constrained to ensure that risks of soil erosion were acceptable. Impacts on net primary productivity (ANPP) varied widely between GCM projections; the average declines from historical climate were 9% in 2030, 7% in 2050 and 14% in 2070. Declines in ANPP were larger at lower‐rainfall locations. Sensitivity of ANPP to changes in rainfall ranged from 0.4 to 1.7, to temperature increase from ?0.15 to +0.07 °C^?1 and to CO₂ increase from 0.11 to 0.32. At most locations the dry summer period lengthened, exacerbating the greater erosion risk due to lower ANPP. Transpiration efficiency of pastures increased by 6–25%, but the proportion of ANPP that could safely be consumed by livestock fell sharply so that operating profit (at constant prices) fell by an average of 27% in 2030, 32% in 2050 and 48% in 2070. This amplification of ANPP reductions into larger profitability declines is likely to generalize to other extensive livestock systems. Profit declines were most marked at drier locations, with operating losses expected at 9 of the 25 locations by 2070. Differences between livestock enterprises were smaller than differences between locations and dates. Future research into climate change impacts on Australian livestock production needs to emphasise the dry margin of the cereal‐livestock zone.     

High level expression and characterization of a novel thermostable, organic solvent tolerant, 1,3-regioselective lipase from Geobacillus sp. strain ARM

The mature ARM lipase gene was cloned into the pTrcHis expression vector and over-expressed in Escherichia coli TOP10 host. The optimum lipase expression was obtained after 18 h post induction incubation with 1.0 mM IPTG, where the lipase activity was approximately 1623-fold higher than wild type. A rapid, high efficient, one-step purification of the His-tagged recombinant lipase was achieved using immobilized metal affinity chromatography with 63.2% recovery and purification factor of 14.6. The purified lipase was characterized as a high active (7092 U mg⁻¹), serine-hydrolase, thermostable, organic solvent tolerant, 1,3-specific lipase with a molecular weight of about 44 kDa. The enzyme was a monomer with disulfide bond(s) in its structure, but was not a metalloenzyme. ARM lipase was active in a broad range of temperature and pH with optimum lipolytic activity at pH 8.0 and 65 °C. The enzyme retained 50% residual activity at pH 6.0-7.0, 50 °C for more than 150 min.     

Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders

The stimuli for neuronal cell death in neurodegenerative disorders are multi-factorial and may include genetic predisposition, environmental factors, cellular stressors such as oxidative stress and free radical production, bioenergy failure, glutamate-induced excitotoxicity, neuroinflammation, disruption of Ca(2+) -regulating systems, mitochondrial dysfunction and misfolded protein accumulation. Cellular stress disrupts functioning of the endoplasmic reticulum (ER), a critical organelle for protein quality control, leading to induction of the unfolded protein response (UPR). ER stress may contribute to neurodegeneration in a range of neurodegenerative disorders. This review summarizes the molecular events occurring during ER stress and the unfolded protein response and it specifically evaluates the evidence suggesting the ER stress response plays a role in neurodegenerative disorders.     

Epidermal growth factor-induced modulation of cytokeratin expression levels influences the morphological phenotype of head and neck squamous cell carcinoma cells

The migratory ability of tumor cells requires cytoskeletal rearrangement processes. Epidermal growth factor receptor (EGFR)-signaling tightly correlates with tumor progression in head and neck squamous cell carcinomas (HNSCCs), and has previously been implicated in the regulation of cytokeratin (CK) expression. In this study, HNSCC cell lines were treated with EGF, and CK expression levels were monitored by Western blot analysis. Changes in cellular morphology were documented by fluorescence- and atomic force microscopy. Some of the cell lines demonstrated an EGF-dependent modulation of CK expression levels. Interestingly, regression of some CK subtypes or initial up-regulation followed by downregulation at higher EGF-levels could also be observed in the tested cell lines. Overall, the influence of EGF on CK expression levels appeared variable and cell-type-dependent. Real-time cellular analysis of EGF-treated and -untreated HNSCC cell lines demonstrated a rise over time in cellular impedance. In three of the EGF-treated HNSCC cell lines, this rise was markedly higher than in untreated controls, whereas in one of the cell lines the gain of cellular impedance was paradoxically reduced after EGF treatment, which was found to correlate with changes in cellular morphology rather than with relevant changes in cellular viability or proliferation. After treating HNSCC cells with EGF, CK filaments frequently appeared diffusely distributed throughout the cytoplasm, and in some cases were found in a perinuclear localization, the latter being reminiscent to observations by other groups. In summary, the data points to a possible role of EGFR in modulating HNSCC cell morphology.     

Safety and Efficacy of Botulinum Toxin to Preserve Gland Function after Radiotherapy in Patients with Head and Neck Cancer: A Prospective,Randomized, Placebo-Controlled,Double-Blinded Phase I Clinical Trial

This prospective, randomized, placebo-controlled, double-blinded phase I clinical trial investigates safety and efficacy of botulinum toxin (BoNT) to preserve gland function after radiotherapy in patients with head and neck cancer. Twelve patients with advanced head and neck cancer were injected with BoNT into the submandibular glands prior to primary radiochemotherapy. Six patients received BoNT/A and 6 patients BoNT/A and B, half of each subgroup into their left and the other half into their right gland. As an internal control, sodium chloride was injected into the respective contralateral gland (placebo). For the evaluation of the salivary gland function, technetium pertechnetate salivary gland scintigraphy was performed before and after the end of radiotherapy. BoNT/A and B were well tolerated. Analysis of the scintigraphic data revealed no statistically significant difference between BoNT and placebo regarding the scintigraphic uptake difference (pBoNT/A = 0.84 and pBoNT/A-B = 0.56 for BoNT/A vs. placebo and BoNT/A-B vs. placebo, respectively). We also found no significant difference in treatment between BoNT and placebo in terms of salivary excretion fraction (pBoNT/A = 0.44; pBoNT/A-B = 0.44). This study demonstrates that BoNT can be safely combined with radiochemotherapy. Dosing and timing of BoNT injection should be further investigated for efficacy analysis.

Trial Registration

German Registry for Clinical Trails DRKS00004595     

Synthesis of 2,3-diaryl-1,3-thiazolidine-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors

A group of 2,3-diaryl-1,3-thiazolidine-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity.     

Protein-free spliceosomal snRNAs catalyze a reaction that resembles the first step of splicing

Splicing of introns from mRNA precursors is a two-step reaction performed by the spliceosome, an immense cellular machine consisting of over 200 different proteins and five small RNAs (snRNAs). We previously demonstrated that fragments of two of these RNAs, U6 and U2, can catalyze by themselves a splicing-related reaction, involving one of the two substrates of the first step of splicing, the branch site substrate. Here we show that these same RNAs can catalyze a reaction between RNA sequences that resemble the 5' splice site and the branch site, the two reactants of the first step of splicing. The reaction is dependent on the sequence of the 5' splice site consensus sequence and the catalytically essential domains of U6, and thus it resembles the authentic splicing reaction. Our results demonstrate the ability of protein-free snRNAs to recognize the sequences involved in the first splicing step and to perform splicing-related catalysis between these two pre-mRNA-like substrates.     

The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance

Tumour cells endure both oncogenic and environmental stresses during cancer progression. Transformed cells must meet increased demands for protein and lipid production needed for rapid proliferation and must adapt to exist in an oxygen‐ and nutrient‐deprived environment. To overcome such challenges, cancer cells exploit intrinsic adaptive mechanisms such as the unfolded protein response (UPR). The UPR is a pro‐survival mechanism triggered by accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), a condition referred to as ER stress. IRE1, PERK and ATF6 are three ER anchored transmembrane receptors. Upon induction of ER stress, they signal in a coordinated fashion to re‐establish ER homoeostasis, thus aiding cell survival. Over the past decade, evidence has emerged supporting a role for the UPR in the establishment and progression of several cancers, including breast cancer, prostate cancer and glioblastoma multiforme. This review discusses our current knowledge of the UPR during oncogenesis, tumour growth, metastasis and chemoresistance.