TGFβ1 rapidly activates Src through a non-canonical redox signaling mechanism.

Transforming growth factor-β1 (TGF-β) is involved in multiple cellular processes through Src activation. In the canonical pathway, Src activation is initiated by pTyr530 dephosphorylation followed by a conformational change allowing Tyr419 auto-phosphorylation. A non-canonical pathway in which oxidation of cysteine allows bypassing of pTyr530 dephosphorylation has been reported. Here, we examined how TGF-β activates Src in H358 cells, a small cell lung carcinoma cell line. TGF-β increased Src Tyr419 phosphorylation, but surprisingly, Tyr530 phosphorylation was increased rather than decreased. Vanadate, a protein tyrosine phosphatase inhibitor, stimulated Src activation itself, but rather than inhibiting Src activation by TGF-β, activation by vanadate was additive with TGF-β showing that pTyr530 dephosphorylation was not required. Thus, the involvement of the non-canonical oxidative activation was suspected. TGF-β increased extracellular H2O2 transiently while GSH-ester and catalase abrogated Src activation by TGF-β. Apocynin, a NADPH oxidase inhibitor, inhibited TGF-β-stimulated H2O2 production. Furthermore, mutation of cysteines to alanine, 248C/A, 277C/A, or 501C/A abrogated, while 490C/A significantly reduced, TGF-β-mediated Src activation. Taken together, the results indicate that TGF-β-mediated Src activation operates largely through a redox dependent mechanism, resulting from enhanced H2O2 production through an NADPH oxidase and that cysteines 248, 277, 490, and 501 are critical for this activation

The Underlying Complexities Impacting Accelerator Decision Making—A Combined Methodological Analysis

Business accelerators play a key role in the initial critical stages of assessment of commercial viability, offering mentorship provision of funding and protection of intellectual property for product development and refinement. However, little is known about the decision making criteria and detailed analysis of the underlying criteria and interdependencies between the key factors used by accelerator organisations to fund start-ups. This study focusses on the decision making criteria utilised by a leading £21M accelerator programme, largely funded by the European Regional Development Fund for initial stage funding and intellectual property protection for product and innovation commercialisation. We incorporate a multi-methodological interpretive based approach based on Day’s ‘Real-Win-Worth’ framework to develop the interrelationships and ranking between the factors. The results highlight the significance and weighting attached to the factors associated with the technical competency of the proposer and evidence of demand existing for the product. We propose a new framework that models the key factor interrelationships offering additional insight to accelerator based decision making

Oxidative stress response and Nrf2 signaling in aging.

Increasing oxidative stress, a major characteristic of aging, has been implicated in a variety of age-related pathologies. In aging, oxidant production from several sources is increased, whereas antioxidant enzymes, the primary lines of defense, are decreased. Repair systems, including the proteasomal degradation of damaged proteins, also decline. Importantly, the adaptive response to oxidative stress declines with aging. Nrf2/EpRE signaling regulates the basal and inducible expression of many antioxidant enzymes and the proteasome. Nrf2/EpRE activity is regulated at several levels, including transcription, posttranslation, and interactions with other proteins. This review summarizes current studies on age-related impairment of Nrf2/EpRE function and discusses the changes in Nrf2 regulatory mechanisms with aging

How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo.

We present arguments for an evolution in our understanding of how antioxidants in fruits and vegetables exert their health-protective effects. There is much epidemiological evidence for disease prevention by dietary antioxidants and chemical evidence that such compounds react in one-electron reactions with free radicals in vitro. Nonetheless, kinetic constraints indicate that in vivo scavenging of radicals is ineffective in antioxidant defense. Instead, enzymatic removal of nonradical electrophiles, such as hydroperoxides, in two-electron redox reactions is the major antioxidant mechanism. Furthermore, we propose that a major mechanism of action for nutritional antioxidants is the paradoxical oxidative activation of the Nrf2 (NF-E2-related factor 2) signaling pathway, which maintains protective oxidoreductases and their nucleophilic substrates. This maintenance of "nucleophilic tone," by a mechanism that can be called "para-hormesis," provides a means for regulating physiological nontoxic concentrations of the nonradical oxidant electrophiles that boost antioxidant enzymes, and damage removal and repair systems (for proteins, lipids, and DNA), at the optimal levels consistent with good health

Mitochondrial biogenesis-associated factors underlie the magnitude of response to aerobic endurance training in rats

Trainability is important in elite sport and in recreational physical activity, and the wide range for response to training is largely dependent on genotype. In this study, we compare a newly developed rat model system selectively bred for low and high gain in running distance from aerobic training to test whether genetic segregation for trainability associates with differences in factors associated with mitochondrial biogenesis. Low response trainer (LRT) and high response trainer (HRT) rats from generation 11 of artificial selection were trained five times a week, 30 min per day for 3 months at 70 % VO2max to study the mitochondrial molecular background of trainability. As expected, we found significant differential for the gain in running distance between LRT and HRT groups as a result of training. However, the changes in VO2max, COX-4, redox homeostasis associated markers (reactive oxygen species (ROS)), silent mating-type information regulation 2 homolog (SIRT1), NAD+/NADH ratio, proteasome (R2 subunit), and mitochondrial network related proteins such as mitochondrial fission protein 1 (Fis1) and mitochondrial fusion protein (Mfn1) suggest that these markers are not strongly involved in the differences in trainability between LRT and HRT. On the other hand, according to our results, we discovered that differences in basal activity of AMP-activated protein kinase alpha (AMPKα) and differential changes in aerobic exercise-induced responses of citrate synthase, carbonylated protein, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1-α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and Lon protease limit trainability between these selected lines. From this, we conclude that mitochondrial biogenesis-associated factors adapt differently to aerobic exercise training in training sensitive and training resistant rats

The characteristics of billows generated by internal solitary waves

The spatial and temporal development of shear-induced overturning billows associated with breaking internal solitary waves is studied by means of a combined laboratory and numerical investigation. The waves are generated in the laboratory by a lock exchange mechanism and they are simulated numerically via a contour-advective semi-Lagrangian method. The properties of individual billows (maximum height attained, time of collapse, growth rate, speed, wavelength, Thorpe scale) are determined in each case, and the billow interaction processes are studied and classified. For broad flat waves, similar characteristics are seen to those in parallel shear flow, but, for waves not at the conjugate flow limit, billow characteristics are affected by the spatially varying wave-induced shear flow. Wave steepness and wave amplitude are shown to have a crucial influence on determining the type of interaction that occurs between billows and whether billow overturning can be arrested. Examples are given in which billows (i) evolve independently of one another, (ii) pair with one another, (iii) engulf/entrain one another and (iv) fail to completely overturn. It is shown that the vertical extent a billow can attain (and the associated Thorpe scale of the billow) is dependent on wave amplitude but that its value saturates once a given amplitude is reached. It is interesting to note that this amplitude is less than the conjugate flow limit amplitude. The number of billows that form on a wave is shown to be dependent on wavelength; shorter waves support fewer but larger billows than their long-wave counterparts for a given stratification.PostprintPeer reviewe

AN INDEPTH EVALUATION ON THE ISSUE OF EXAMINATION MALPRACTICE IN NIGERIA

There is a decline in the quality of graduates from secondary schools in Nigeria. A situation where some secondary school graduates cannot write a very good letter is a cause for concern. Secondary School teachers, parents and the society have always complained about the quality of school products. All these are alarming signals which portends danger for the country. A number of issues could have led to these problems and the most pronounced among them is examination malpractice. Examination malpractice has eaten deep into the Nigeria education system. The purpose of this study therefore was to examine the issue of examination malpractice in Nigeria. The use of secondary sources of data was the main method of data collection adopted in this research work. The secondary sources adopted in this study include materials like Newspapers, magazines, textbooks, internet, journals, government publications, official documents etc. After analyzing the data, it was deduced that collusion among candidates, impersonation, giraffing, inscription, scientific malpractice and bribery were some of the forms of examination malpractice in Nigeria. This study also found that fear of failure, craze for certificates, desire of parents to choose the profession and university, pressure on students to pursue courses which they have no aptitude for were some of the causes of examination malpractice in Nigeria. This study also found that the examination malpractice has a negative effect on the society, leads to irreversible loss of credibility, has negative consequences on the individuals and institutions of learning, leads to moral decadence and brain drain, leads to corruption, it discourages hard work among students. This study also found that measures of curbing examination malpractice include: societal reengineering and re-orientation to revamp moral values, retraining and reassessment of teachers, appropriate recognition and remuneration of teachers and examination officials. Curbing examination malpractice depended on our will power. This study revealed that examination malpractice is not perpetrated by Angels but human beings. Based on the findings above, this study recommended that aggressive campaign should therefore be mounted, educating all the stakeholders about the dangers in engaging in the act and let them be informed of the dignity in having a clean examination system, the Federal Government should try and make the salary of teachers reasonable, qualityand affordable education should be made available for all, this study concluded that Parents should not celebrate success without a commensurate input and that examination malpractice should be discouraged entirely

The Calcineurin Antagonist, RCAN1-4 is Induced by Exhaustive Exercise in Rat Skeletal Muscle

International audienceThe aim of this work was to study the regulation of the calcineurin antagonist regulator of calcineurin 1 (RCAN1) in rat skeletal muscles after exhaustive physical exercise, which is a physiological modulator of oxidative stress. Three skeletal muscles, namely extensor digitorum longus (EDL), gastrocnemius, and soleus, were investigated. Exhaustive exercise increased RCAN1-4 protein levels in EDL and gastrocnemius, but not in soleus. Protein oxidation as an index of oxidative stress was increased in EDL and gastrocnemius, but remained unchanged in soleus. However, lipid peroxidation was increased in all three muscles. CuZnSOD and catalase protein levels were increased at 3 h postexercise in soleus, whereas they remained unchanged in EDL and gastrocnemius. Calcineurin enzymatic activity declined in EDL and gastrocnemius but not in soleus, and its protein expression was decreased in all three muscles. The level of PGC1-α protein remained unchanged, whereas the protein expression of the transcription factor NFATc4 was decreased in all three muscles. Adiponectin expression was increased in all three muscles. RCAN1-4 expression in EDL and gastrocnemius muscles was augmented by the oxidative stress generated from exhaustive exercise. We propose that increased RCAN1-4 expression and the signal transduction pathways it regulates represent important components of the physiological adaptation to exercise-induced oxidative stress