TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAIL-induced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis.     

Exploitation of synthetic-derived wheats through osmotic stress responses for drought tolerance improvement

The development of drought tolerant wheat cultivars has been slow due to lack of understanding the diagnostic physiological parameters associated with improved productivity under water stress. We evaluated responses to PEG induced osmotic stress under hydroponics in D-genome synthetic derived and bread wheat germplasm with the main aim to unravel and identify some promising attributes having role in stress tolerances. Genotypes used in this study differed in their morpho-physiological and biochemical attributes. Tolerant genotypes exhibited the ability to ameliorate harmful effects of PEG induced osmotic stress through better osmotic adjustment achieved through substantial relative water content (RWC), lowered osmotic potential, relatively stable root length having maximum water extraction capacity, significant increase in osmoprotectant concentration and relatively enhanced antioxidant activities. The results clearly revealed the importance of synthetic derivatives over check cultivars and conventional wheats in terms of osmotic stress responses. Interestingly, synthetic-derived advanced lines with Aegilops tauschii in its parentage including AWL-02, AWL-04 and AWL-07 proved superior over the best rainfed check cultivar (Wa-01). It was concluded that synthetic-derived wheats has great potential to improve a range of stress adaptive traits. It could, therefore, be recommended to be a useful strategy for allowing modern bread wheat to become adapted to a wider range of environments in future climate change scenarios.     

A putative poplar PP2C-encoding gene negatively regulates drought and abscisic acid responses in transgenic Arabidopsis thaliana

Key message

Here we link for the first time a poplar gene with putative function in ABA signaling to the regulation of drought responses, providing a target for drought tolerance improvement in poplars.

Abstract

Populus species are valued for their fast growth and are cultivated widely. Many of the commonly used species and hybrids are, however, regarded as drought sensitive, which poses a problem for large-scale cultivation particularly in light of climate change-induced drought spells in areas of poplar growth. While many hundreds of drought-induced genes have been identified in Populus species, very little is known about the genes and the signaling process that leads to a drought response in these species. Based on sequence similarity, the poplar G059200 gene is a potential ortholog of AtPP2CA, an inhibitor of drought and abscisic acid (ABA) responses in Arabidopsis thaliana. To test if G059200 has a similar function, we generated transgenic A. thaliana plants overexpressing this gene. These transgenic lines exhibited reduced responses to exogenous ABA and reduced tolerance to osmotic stress. Finally, drought tolerance of plants was also significantly reduced. Taken together, these data provide evidences that G059200 acts as a negative regulator of ABA responses. The ability to negatively regulate drought stress responses suggests that G059200 may be targeted for drought tolerance breeding, for example, by identification of individuals harboring natural or induced loss-of-function alleles, or by RNA interference technology, to generate poplar plants with reduced activity of G059200.     

Pathophysiological characterization of asthma transitions across adolescence

Background

Adolescence is a period of change, which coincides with disease remission in a significant proportion of subjects with childhood asthma. There is incomplete understanding of the changing characteristics underlying different adolescent asthma transitions. We undertook pathophysiological characterization of transitional adolescent asthma phenotypes in a longitudinal birth cohort.

Methods

The Isle of Wight Birth Cohort (N = 1456) was reviewed at 1, 2, 4, 10 and 18-years. Characterization included questionnaires, skin tests, spirometry, exhaled nitric oxide, bronchial challenge and (in a subset of 100 at 18-years) induced sputum. Asthma groups were “never asthma” (no asthma since birth), “persistent asthma” (asthma at age 10 and 18), “remission asthma” (asthma at age 10 but not at 18) and “adolescent-onset asthma” (asthma at age 18 but not at age 10).

Results

Participants whose asthma remitted during adolescence had lower bronchial reactivity (odds ratio (OR) 0.30; CI 0.10 -0.90; p = 0.03) at age 10 plus greater improvement in lung function (forced expiratory flow 25-75% gain: 1.7 L; 1.0-2.9; p = 0.04) compared to persistent asthma by age 18. Male sex (0.3; 0.1-0.7; p < 0.01) and lower acetaminophen use (0.4; 0.2-0.8; p < 0.01) independently favoured asthma remission, when compared to persistent asthma. Asthma remission had a lower total sputum cell count compared to never asthma (31.5 [25–75 centiles] 12.9-40.4) vs. 47.0 (19.5-181.3); p = 0.03). Sputum examination in adolescent-onset asthma showed eosinophilic airway inflammation (3.0%, 0.7-6.6), not seen in persistent asthma (1.0%, 0–3.9), while remission group had the lowest sputum eosinophil count (0.3%, 0–1.4) and lowest eosinophils/neutrophils ratio of 0.0 (Interquartile range: 0.1).

Conclusion

Asthma remission during adolescence is associated with lower initial BHR and greater gain in small airways function, while adolescent-onset asthma is primarily eosinophilic.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0153-7) contains supplementary material, which is available to authorized users.     

Patterns of ion excretion and survival in two stoloniferous arid zone grasses

Desert plants show specific mechanisms to thrive under prevailing harsh conditions. To study the survival mechanism(s) in native desert plant species, Lesser Cholistan desert in Pakistan was surveyed and two potential salt secretory grass species, Aeluropus lagopoides and Ochthochloa compressa , were selected from five saline sites. Both these grasses responded differentially to saline environments by showing specialized mechanisms of survival including excretion of toxic ions through trichomes, vesicular and glandular hairs through leaf surface. In A. lagopoides , salt tolerance was associated with excreted Na⁺ concentration through leaf surface and accumulation of useful ions like Ca²⁺ and K⁺ in the shoot. Contrarily, O. compressa excreted all the ions through leaves without discriminating among toxic or beneficial ions. Results suggested that A. lagopoides was more successfully adapted to saline desert environments than O. compressa by excretion of excessive toxic ions and retention of Ca²⁺ and K⁺ in the shoot. This appears to be an adaptive character of the former species to successfully thrive in harsh desert conditions.     

A PSHaver for centromeric histones

In this issue of Molecular Cell, Hewawasam et al. (2010) and Ranjitkar et al. (2010) identify and characterize Psh1, an E3 ubiquitin ligase that specifically targets the centromeric histone Cse4 in budding yeast and limits its misincorporation at noncentromeric regions.     

Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability

Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease-causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32-p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development.