Effects of salt stress on growth, photosynthesis and nitrogen fixation in chick-pea (Cicer arietinum L.)

Plants of chick-pea (Cicer arietinum L. cv. ILC1919) inoculated with Mesorhizobium ciceri strain ch-191 were grown in a controlled environmental chamber, and were administered salt (0, 50, 75, and 100 mM NaCl) during the vegetative period. Four harvests (4, 7, 11, and 14d after treatment) were analysed. The aim was to ascertain whether the negative effect of saline stress on nitrogen fixation is due to a limitation on the photosynthate supply to the nodule or a limitation on the nodular metabolism which sustains nitrogenase activity.Plant growth was affected only by the highest NaCl concentration, whereas nitrogenase activity was affected from 50 mM. At the first harvest, Rubisco, PEPC and MDH activities in leaves rose with salt, but fell during the following harvests. The increase of PEPC and MDH in nodules at the two first samplings was clearly related to salt concentration. While 50 mM NaCl increased GS and GOGAT in nodules at some harvests, 100 mM strongly inhibited these activities at all the harvests. The accumulation of proline, amino acids and carbohydrates was clearly related to salt especially in the leaves, whereas in the nodules the protein content was boosted by salt. Although photosynthesis declined with NaCl, the response of nitrogen fixation to salt was more pronounced. This situation, together with carbohydrate accumulation, suggests that the lack of photosynthate does not cause the inhibition of nitrogenase activity under this type of stress. The similar trend observed for the PEPC-MDH pathway and the ARA support the hypothesis concerning the limitation in the supply of energy substrate, mainly malate, to the bacteroids. The accumulation of compatible solutes is more a consequence of damage produced by salt stress than of a protective strategy.     

Analysis of the sorting signals directing NADH-cytochrome b5 reductase to two locations within yeast mitochondria.

Mitochondrial NADH-cytochrome b5 reductase (Mcr1p) is encoded by a single nuclear gene and imported into two different submitochondrial compartments: the outer membrane and the intermembrane space. We now show that the amino-terminal 47 amino acids suffice to target the Mcr1 protein to both destinations. The first 12 residues of this sequence function as a weak matrix-targeting signal; the remaining residues are mostly hydrophobic and serve as an intramitochondrial sorting signal for the outer membrane and the intermembrane space. A double point mutation within the hydrophobic region of the targeting sequence virtually abolishes the ability of the precursor to be inserted into the outer membrane but increases the efficiency of transport into the intermembrane space. Import of Mcr1p into the intermembrane space requires an electrochemical potential across the inner membrane, as well as ATP in the matrix, and is strongly impaired in mitochondria lacking Tom7p or Tim11p, two components of the translocation machineries in the outer and inner mitochondrial membranes, respectively. These results indicate that intramitochondrial sorting of the Mcr1 protein is mediated by specific interactions between the bipartite targeting sequence and components of both mitochondrial translocation systems.     

Surface characteristics of lactobacilli isolated from human vagina

In the present paper, the taxonomic classification of 134 lactobacilli isolates from vaginal samples of 200 women of Tucumán, Argentina, is reported. They were clustered in three metabolic groups of the genus Lactobacillus, most belonging to the obligately homofermentative group (56%), mainly represented by Lactobacillus delbrueckii subsp. delbrueckii and L. acidophilus. In the facultatively heterofermentative group (24%), the dominant species were L. paracasei subsp. paracasei and L. agilis, and in the obligately heterofermentative group (20%), L. brevis was the dominant species. All strains were studied for surface characteristics and adhesion-predicting properties. A correlation between the methods employed for hydrophobicity testing of the different isolates (Microbial Adhesion to Hydrocarbons and Salt Aggregation Test) is reported. Most strains were highly hydrophobic. Their hemagglutination capability with human erythrocytes was also tested, which was positive only for a few strains. Some isolates were self-aggregating. From our results, strains that shared the properties assayed were selected for further testing of some other desirable characteristics, such as antagonistic substance production, adhesion to biological substrates, and appropriate technological properties, to suggest the elaboration of a probiotic for the vaginal tract.     

Cardiovascular Toxicity of Multi-Tyrosine Kinase Inhibitors in Advanced Solid Tumors: A Population-Based Observational Study

Background

Treatment with small molecule tyrosine kinase inhibitors (TKIs) has improved survival in many cancers, yet has been associated with an increased risk of adverse events. Warnings of cardiovascular events are common in drug labels of many TKIs. Despite these warnings, cardiovascular toxicity of patients treated with TKIs remains unclear. Here, we evaluate the cardiovascular outcomes of advanced cancer patients treated with small molecule tyrosine kinase inhibitors.

Methods

A population based cohort study was undertaken involving adults aged >18 years in Ontario, Canada, diagnosed with any advanced malignancy between 2006 and 2012. Data were extracted from linked administrative governmental databases. Adults with advanced cancer receiving TKIs were identified and followed throughout the time period. The main outcomes of interest were rates of hospitalization for ischemic heart disease (acute myocardial infarction and angina) or cerebrovascular accidents and death.

Results

1642 patients with a mean age of 62.5 years were studied; 1046 were treated with erlotinib, 166 with sorafenib and 430 with sunitinib. Over the 380 day median follow-up period (range 6-1970 days), 1.1% of all patients had ischemic heart events, 0.7% had cerebrovascular accidents and 72.1% died. Rates of cardiovascular events were similar to age and gender-matched individuals without cancer. In a subgroup analysis of treatment patients with a prior history of ischemic heart disease, 3.3% had ischemic heart events while 1.2% had cerebrovascular accidents.

Conclusions

TKIs do not appear to increase the cause-specific hazard of ischemic heart disease and cerebrovascular accidents compared to age and gender-matched individuals without advanced cancer.     

Y-linked Mendelian inheritance of giant and dwarf male morphs in shell-brooding cichlids

Behavioural variation among conspecifics is typically contingent on individual state or environmental conditions. Sex-specific genetic polymorphisms are enigmatic because they lack conditionality, and genes causing adaptive trait variation in one sex may reduce Darwinian fitness in the other. One way to avoid such genetic antagonism is to control sex-specific traits by inheritance via sex chromosomes. Here, controlled laboratory crossings suggest that in snail-brooding cichlid fish a single locus, two-allele polymorphism located on a sex-linked chromosome of heterogametic males generates an extreme reproductive dimorphism. Both natural and sexual selection are responsible for exceptionally large body size of bourgeois males, creating a niche for a miniature male phenotype to evolve. This extreme intrasexual dimorphism results from selection on opposite size thresholds caused by a single ecological factor, empty snail shells used as breeding substrate. Paternity analyses reveal that in the field parasitic dwarf males sire the majority of offspring in direct sperm competition with large nest owners exceeding their size more than 40 times. Apparently, use of empty snail shells as breeding substrate and single locus sex-linked inheritance of growth are the major ecological and genetic mechanisms responsible for the extreme intrasexual diversity observed in Lamprologus callipterus.     

Biomeasures and mechanistic modeling highlight PK/PD risks for a monoclonal antibody targeting Fn14 in kidney disease

Discovery of the upregulation of fibroblast growth factor-inducible-14 (Fn14) receptor following tissue injury has prompted investigation into biotherapeutic targeting of the Fn14 receptor for the treatment of conditions such as chronic kidney diseases. In the development of monoclonal antibody (mAb) therapeutics, there is an increasing trend to use biomeasures combined with mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling to enable decision making in early discovery. With the aim of guiding preclinical efforts on designing an antibody with optimized properties, we developed a mechanistic site-of-action (SoA) PK/PD model for human application. This model incorporates experimental biomeasures, including concentration of soluble Fn14 (sFn14) in human plasma and membrane Fn14 (mFn14) in human kidney tissue, and turnover rate of human sFn14. Pulse-chase studies using stable isotope-labeled amino acids and mass spectrometry indicated the sFn14 half-life to be approximately 5 hours in healthy volunteers. The biomeasures (concentration, turnover) of sFn14 in plasma reveals a significant hurdle in designing an antibody against Fn14 with desired characteristics. The projected dose (>1 mg/kg/wk for 90% target coverage) derived from the human PK/PD model revealed potential high and frequent dosing requirements under certain conditions. The PK/PD model suggested a unique bell-shaped relationship between target coverage and antibody affinity for anti-Fn14 mAb, which could be applied to direct the antibody engineering towards an optimized affinity. This investigation highlighted potential applications, including assessment of PK/PD risks during early target validation, human dose prediction and drug candidate optimization.     

Activation of the PI3K/mTOR/AKT Pathway and Survival in Solid Tumors: Systematic Review and Meta-Analysis

Background

Aberrations in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components of this pathway. However the prognostic value of these aberrations is unclear.

Methods

PubMed was searched for studies evaluating the association between activation of the PI3K/mTOR/AKT pathway (defined as PI3K mutation [PIK3CA], lack of phosphatase and tensin homolog [PTEN] expression by immunohistochemistry or western-blot or increased expression/activation of downstream components of the pathway by immunohistochemistry) with overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (OR) for death at 5 years. Data were pooled using the Mantel-Haenszel random-effect model.

Results

Analysis included 17 studies. Activation of the PI3K/mTOR/AKT pathway was associated with significantly worse 5-year survival (OR:2.12, 95% confidence intervals 1.42–3.16, p<0.001). Loss of PTEN expression and increased expression/activation of downstream components were associated with worse survival. No association between PIK3CA mutations and survival was observed. Differences between methods for assessing activation of the PI3K/mTOR/AKT pathway were statistically significant (p = 0.04). There was no difference in the effect of up-regulation of the pathway on survival between different cancer sites (p = 0.13).

Conclusion

Activation of the PI3K/AKT/mTOR pathway, especially if measured by loss of PTEN expression or increased expression/activation of downstream components is associated with poor survival. PIK3CA mutational status is not associated with adverse outcome, challenging its value as a biomarker of patient outcome or as a stratification factor for patients treated with agents acting on the PI3K/AKT/mTOR pathway.     

Maturation, Spawning and Development in Siphonaria Pectinata Linnaeus (Gastropoda: Pulmonata) at Gibraltar

A comparative study of some aspects of the reproductive biologyof Siphonaria pectinata was carried out at Gibraltar. Maturationoccurred at 5-6 mm shell length corresponding to an age of 6-12months. At the more sheltered Atlantic site spawning was evidentfrom March to June 1992 with peak spawning occurring in May-June1992. The patterns of spawning activity for the following twoyears were very similar. Egg ribbons were very scarce at themore exposed Mediterranean site and were found in considerablyless quantities than at the Atlantic site. Individuals at bothsites contained mature eggs in their gonads at the onset, andthen throughout the duration of the spawning season, but exhibitedspent gonads by October. The spawn of S. pectinata consistedof small oval ribbons filled with numerous egg-shaped capsulesspaced irregularly in a jelly-like matrix. Spawn was depositedmainly away from the home scar in shallow depressions, cracksand crevices and between barnacles and mussels. S. pectinataexhibited planktonic development. The fertilised eggs took between14 and 21 days to develop at ambient temperature (14-19°),and hatched as free-swimming planktotrophic veligers. The timingof spawning activity and the placement of egg masses in protectivemicrohabitats on the shore are discussed in terms of adaptationsto reduce desiccation stress, predation and possible food shortages.The mode of development in S. pectinata is placed in contextwith current theories regarding siphonariid ancestry and evolution. (Received 6 January 1998; accepted 25 June 1998)     

Topical Application of a Platelet Activating Factor Receptor Agonist Suppresses Phorbol Ester-Induced Acute and Chronic Inflammation and Has Cancer Chemopreventive Activity in Mouse Skin

Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-Kit ^W-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-Kit ^W-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.