Environmental transfer parameters of strontium for soil to cow milk pathway for tropical monsoonal climatic region of the Indian subcontinent.

The radionuclide transfer between compartments is commonly described by transfer parameters representing the ratio of concentrations of an element in two compartments for equilibrium conditions. This is a comprehensive study on the soil-to-grass transfer factor (Fv) and grass-to-cow milk transfer coefficient (Fm) for stable strontium (Sr) for soil-grass (pasture)-cow (Bos taurus) milk environmental pathway under field conditions for a high rainfall tropical monsoonal climatic region of the Indian subcontinent. The study was conducted in the vicinity of the Kaiga nuclear power plant (NPP), situated ~ 58 km inland of the West Coast of the Indian subcontinent. A grass field was developed exclusively for this study, and two cows of the native breed were raised to graze on it. The soil, grass, and milk were analyzed to evaluate the Fv and the Fm values for the stable Sr. For comparison, several pasture lands and the cows raised by the villagers and a dairy farm were also studied. The Fv values were in the range 0.18-8.6, the geometric mean (GM) being 1.8. The correlations of Fv values with a range of physicochemical parameters are presented. The GM values for Fm were 2.2 × 10-3 d L-1 and 7.2 × 10-3 d L-1 for the two cows raised for this study, 2.6 × 10-3 d L-1 for those raised by the villagers, and 4.2 × 10-3 d L-1 for the dairy farm. The site-specific Fm value for the region was determined as 3.2 × 10-3 d L-1. The concentration ratio (CR), defined as the ratio of Sr concentration in milk to that in feed under equilibrium conditions, exhibited less variability (1.8 × 10-2-5.4 × 10-2) among the three categories of cows.

Cumulative deamidations of the major lens protein γS-crystallin increase its aggregation during unfolding and oxidation.

Age-related lens cataract is the major cause of blindness worldwide. The mechanisms whereby crystallins, the predominant lens proteins, assemble into large aggregates that scatter light within the lens, and cause cataract, are poorly understood. Due to the lack of protein turnover in the lens, crystallins are long-lived. A major crystallin, γS, is heavily modified by deamidation, in particular at surface-exposed N14, N76, and N143 to introduce negative charges. In this present study, deamidated γS was mimicked by mutation with aspartate at these sites and the effect on biophysical properties of γS was assessed via dynamic light scattering, chemical and thermal denaturation, hydrogen-deuterium exchange, and susceptibility to disulfide cross-linking. Compared with wild type γS, a small population of each deamidated mutant aggregated rapidly into large, light-scattering species that contributed significantly to the total scattering. Under partially denaturing conditions in guanidine hydrochloride or elevated temperature, deamidation led to more rapid unfolding and aggregation and increased susceptibility to oxidation. The triple mutant was further destabilized, suggesting that the effects of deamidation were cumulative. Molecular dynamics simulations predicted that deamidation augments the conformational dynamics of γS. We suggest that these perturbations disrupt the native disulfide arrangement of γS and promote the formation of disulfide-linked aggregates. The lens-specific chaperone αA-crystallin was poor at preventing the aggregation of the triple mutant. It is concluded that surface deamidations cause minimal structural disruption individually, but cumulatively they progressively destabilize γS-crystallin leading to unfolding and aggregation, as occurs in aged and cataractous lenses.

Comparison of response surface methodology and artificial neural network to enhance the release of reducing sugars from non-edible seed cake by autoclave assisted HCl hydrolysis.

In the current investigation, statistical approaches were adopted to hydrolyse non-edible seed cake (NESC) of Pongamia and optimize the hydrolysis process by response surface methodology (RSM). Through the RSM approach, the optimized conditions were found to be 1.17%v/v of HCl concentration at 54.12 min for hydrolysis. Under optimized conditions, the release of reducing sugars was found to be 53.03 g/L. The RSM data were used to train the artificial neural network (ANN) and the predictive ability of both models was compared by calculating various statistical parameters. A three-layered ANN model consisting of 2:12:1 topology was developed; the response of the ANN model indicates that it is precise when compared with the RSM model. The fit of the models was expressed with the regression coefficient R2, which was found to be 0.975 and 0.888, respectively, for the ANN and RSM models. This further demonstrated that the performance of ANN was better than that of RSM.

Estimation of air-to-grass mass interception factors for iodine.

Air-to-grass mass interception factors for radionuclide are important basic input parameter for the estimation of radiation dose to the public around a nuclear power plant. In this paper, we present the determination of air-to- grass mass interception factors for iodine using a 2 m × 2 m × 2 m (l × b × h) size environmental chamber. The temperature, humidity, and rainfall inside the environmental chamber was controlled to required values to simulate different environmental conditions. Grass (Pennisetum purpureum, Schum), grown in pots, was kept inside the environmental chamber and stable iodine in elemental form was sublimed quickly inside the chamber to simulate an accidental release of iodine to the environment. The concentration of iodine in the air was measured periodically by drawing air through a bubbling setup, containing 1% sodium carbonate solution. The mass interception factor for dry deposition varied in the range of 0.25-7.7 m2 kg-1 with mean value of 2.2 m2 kg-1 with respect to fresh weight of grass, and that due to wet deposition varied in the range of 0.6-4.8 m2 kg-1 with mean value of 2.3 m2 kg-1. The mass interception factor was inversely correlated with the total iodine deposited through dry deposition as well as with the rainfall.

Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins.

The rapidly growing recognition of the role of oncogenic ROS1 fusion proteins in the malignant transformation of multiple cancers, including lung adenocarcinoma, cholangiocarcinoma, and glioblastoma, is driving efforts to develop effective ROS1 inhibitors for use as molecularly targeted therapy. Using a multidisciplinary approach involving small molecule screening in combination with in vitro and in vivo tumor models, we show that foretinib (GSK1363089) is a more potent ROS1 inhibitor than crizotinib (PF-02341066), an ALK/ROS inhibitor currently in clinical evaluation for lung cancer patients harboring ROS1 rearrangements. Whereas crizotinib has demonstrated promising early results in patients with ROS1-rearranged non-small-cell lung carcinoma, recently emerging clinical evidence suggests that patients may develop crizotinib resistance due to acquired point mutations in the kinase domain of ROS1, thus necessitating identification of additional potent ROS1 inhibitors for therapeutic intervention. We confirm that the ROS1(G2032R) mutant, recently reported in clinical resistance to crizotinib, retains foretinib sensitivity at concentrations below safe, clinically achievable levels. Furthermore, we use an accelerated mutagenesis screen to preemptively identify mutations in the ROS1 kinase domain that confer resistance to crizotinib and demonstrate that these mutants also remain foretinib sensitive. Taken together, our data strongly suggest that foretinib is a highly effective ROS1 inhibitor, and further clinical investigation to evaluate its potential therapeutic benefit for patients with ROS1-driven malignancies is warranted.

Studies on soil to grass transfer factor (Fv) and grass to milk transfer coefficient (Fm) for cesium in Kaiga region.

Detailed studies were carried out to establish site-specific soil to grass transfer factors (Fv) and grass to cow milk transfer coefficients (Fm) for radioactive cesium ((137)Cs) and stable cesium (Cs) for Kaiga region, where a nuclear power station has been in operation for more than 10 years. The study included adopted cows, cows of local farmers, and cows from the dairy farm. A grass field was developed specifically for the study and 2 local breed cows were adopted and allowed to graze in this grass field. The soil and grass samples were collected regularly from this field and analyzed for the concentrations of (137)Cs and stable Cs to evaluate the soil to grass Fv values. The milk samples from the adopted cows were analyzed for the (137)Cs and stable Cs concentrations to evaluate Fm values. For comparison, studies were also carried out in dominant grazing areas in different villages around the nuclear power plant and the cows of local farmers which graze in these areas were identified and milk samples were collected and analyzed regularly. The geometric mean values of Fv were found to be 1.1 × 10(-1) and 1.8 × 10(-1) for (137)Cs and stable Cs, respectively. The Fm of (137)Cs had geometric mean values of 1.9 × 10(-2) d L(-1) and 4.6 × 10(-2) d L(-1), respectively, for adopted Cows 1 and 2; 1.7 × 10(-2) d L(-1) for the cows of local farmers, and 4.0 × 10(-3) d L(-1) for the dairy farm cows. The geometric mean values of Fm for stable Cs were similar to those of (137)Cs. The Fm value for the dairy farm cows was an order of magnitude lower than those for local breed cows. The Fm values observed for the local breed cows were also an order of magnitude higher when compared to the many values reported in the literature and in the IAEA publication. Possible reasons for this higher Fm values were identified. The correlation between Fv and Fm values for (137)Cs and stable Cs and their dependence on the potassium content ((40)K and stable K) in the soil and grass were also studied. In order to estimate the ingestion dose accurate data of the dietary habits of the population was necessary and this data was collected through a well planned demographic survey. The internal doses to a child due to the ingestion of (137)Cs along with the milk of the local cows and from the dairy farm were found to be 0.29 µSv y(-1) and 0.04 µSv y(-1),while that to an adult were 0.39 µSv y(-1) and 0.05 µSv y(-1), respectively.

Soil to rice transfer factors for (226)Ra, (228)Ra, (210)Pb, (40)K and (137)Cs: a study on rice grown in India.

India is the second largest producer of rice (Oryza sativa L.) in the world and rice is an essential component of the diet for a majority of the population in India. However, detailed studies aimed at the evaluation of radionuclide transfer factors (F(v)) for the rice grown in India are almost non-existent. This paper presents the soil to rice transfer factors for natural ((226)Ra, (228)Ra, (40)K, and (210)Pb) and artificial ((137)Cs) radionuclides for rice grown in natural field conditions on the West Coast of India. A rice field was developed very close to the Kaiga nuclear power plant and the water required for this field was drawn from the cooling water discharge canal of the power plant. For a comparative study of the radionuclide transfer factors, rice samples were also collected from the rice fields of nearby villages. The study showed that the (226)Ra and (228)Ra activity concentrations were below detection levels in different organs of the rice plant. The soil to un-hulled rice grain (40)K transfer factor varied in the range of 6.5 × 10(-1) to 2.9 with a mean of 0.15 × 10(1), and of (210)Pb varied in the range of <1.2 × 10(-2) to 8.1 × 10(-1) with a mean of 1.4 × 10(-1), and of (137)Cs varied in the range of 6.6 × 10(-2) to 3.4 × 10(-1) with a mean of 2.1 × 10(-1). The mean values of un-hulled grain to white rice processing retention factors (F(r)) were 0.12 for (40)K, 0.03 for (210)Pb, and 0.14 for (137)Cs. Using these processing retention factors, the soil to white rice transfer factors were estimated and these were found to have mean values of 1.8 × 10(-1), 4.2 × 10(-3), and 3.0 × 10(-2) for (40)K, (210)Pb, and (137)Cs, respectively. The study has shown that the transfer of (40)K was higher for above the ground organs than for the root, but (210)Pb and (137)Cs were retained in the root and their transfer to above the ground organs of the rice plant is significantly lower.

Folding pathway mediated by an intramolecular chaperone: intrinsically unstructured propeptide modulates stochastic activation of subtilisin.

Several secreted proteases are synthesized with N-terminal propeptides that function as intramolecular chaperones (IMCs) and direct the folding of proteases to their native functional states. Using subtilisin E as our model system, we had earlier established that (i) release and degradation of the IMC from its complex with the protease upon completion of folding is the rate-determining step to protease maturation and, (ii) IMC of SbtE is an extremely charged, intrinsically unstructured polypeptide that adopts an alpha-beta structure only in the presence of the protease. Here, we explore the mechanism of IMC release and the intricate relationship between IMC structure and protease activation. We establish that the release of the first IMC from its protease domain is a non-deterministic event that subsequently triggers an activation cascade through trans-proteolysis. By in silico simulation of the protease maturation pathway through application of stochastic algorithms, we further analyze the sub-stages of the release step. Our work shows that modulating the structure of the IMC domain through external solvent conditions can vary both the time and randomness of protease activation. This behavior of the protease can be correlated to varying the release-rebinding equilibrium of IMC, through simulation. Thus, a delicate balance underlies IMC structure, release, and protease activation. Proteases are ubiquitous enzymes crucial for fundamental cellular processes and require deterministic activation mechanisms. Our work on SbtE establishes that through selection of an intrinsically unstructured IMC domain, nature appears to have selected for a viable deterministic handle that controls a fundamentally random event. While this outlines an important mechanism for regulation of protease activation, it also provides a unique approach to maintain industrially viable subtilisins in extremely stable states that can be activated at will.