Unexpected cell type-dependent effects of autophagy on polyglutamine aggregation revealed by natural genetic variation in C. elegans.

BACKGROUND: Monogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. While natural genetic variants may pinpoint plastic networks amenable to intervention, the mechanisms by which they impact individual susceptibility to proteotoxicity are still largely unknown. RESULTS: We have previously shown that natural variation modifies polyglutamine (polyQ) aggregation phenotypes in C. elegans muscle cells. Here, we find that a genomic locus from C. elegans wild isolate DR1350 causes two genetically separable aggregation phenotypes, without changing the basal activity of muscle proteostasis pathways known to affect polyQ aggregation. We find that the increased aggregation phenotype was due to regulatory variants in the gene encoding a conserved autophagy protein ATG-5. The atg-5 gene itself conferred dosage-dependent enhancement of aggregation, with the DR1350-derived allele behaving as hypermorph. Surprisingly, increased aggregation in animals carrying the modifier locus was accompanied by enhanced autophagy activation in response to activating treatment. Because autophagy is expected to clear, not increase, protein aggregates, we activated autophagy in three different polyQ models and found a striking tissue-dependent effect: activation of autophagy decreased polyQ aggregation in neurons and intestine, but increased it in the muscle cells. CONCLUSIONS: Our data show that cryptic natural variants in genes encoding proteostasis components, although not causing detectable phenotypes in wild-type individuals, can have profound effects on aggregation-prone proteins. Clinical applications of autophagy activators for aggregation diseases may need to consider the unexpected divergent effects of autophagy in different cell types

Role of Positive and Negative Urgency and Social Context on Problematic Alcohol Use Behaviors

poster abstractSocial context influences drinking behaviors; in particular, problematic alcohol use among adolescents and young adults is more frequent in those who drink in more social contexts or who drink for social reasons. Moreover, although positive and negative urgency (i.e., the tendency to act rashly in response to extreme positive or negative emotional states, respectively) also relate to problematic alcohol use, it is unclear whether these impulsivity traits affect problematic alcohol use through social context. As such, the current study examined how positive and negative urgency influence problematic alcohol consumption through the social context of drinking. Participants (n = 348, n = 70 men; Mean age = 20 (SD= 4.5); 78.2% Caucasian) were recruited from the Introduction to Psychology course from IUPUI and received course credit for the completion of an online survey. A series of correlation and mediation analyses were conducted. Problematic alcohol use was significantly related to positive urgency (r=0.33, p<.001) and negative urgency (r= 0.29, p<.001). Although contextual drinking factors did not mediate the relationship between urgency and problematic alcohol use, the relationship between urgency and problematic alcohol use was significantly mediated by the endorsement of social drinking motives (e.g., I drink in order to be more social) (indirect effect of positive urgency b = 1.85, indirect effect of negative urgency b =2.02). Even though social drinking context was not a significant mediator, likely due to very few people reporting drinking in isolation in the current sample, the endorsement of drinking for social reasons might partially explain how urgency influences problematic alcohol use. In this way, intervening on social drinking motives might mitigate the effects of urgency on problematic alcohol use, particularly among college students at risk for alcohol use problems

U-Pb Geochronology, Sr–Nd Geochemistry, Petrogenesis and Tectonic Setting of Gandab Volcanic Rocks, Northeast Iran

This paper addresses U-Pb geochronology, Sr-Nd geochemistry, petrogenesis and tectonic setting in the Gandab volcanic rocks. The Gandab volcanic rocks belong to the Sabzevar zone magmatic arc (northeastern Iran). Petrographically, all the studied volcanic rocks indicate porphyritic textures with phenocrysts of plagioclase, K-feldespar, hornblende, pyroxene, and magnetite which are embedded in a fine to medium grained groundmass. As well, amygdaloidal, and poikilitic textures are seen in some rocks. The standard chemical classifications show that the studied rocks are basaltic trachyandesite, trachyandesite, trachyte, and trachydacite. Major elements reveal that the studied samples are metaluminous and their alumina saturation index varies from 0.71 to 1.02. The chondrite-normalized rare-earth element and mantle-normalized trace-element patterns show enrichment in light rare-earth elements (LREE) relative to heavy rare-earth elements (HREE) and in large ion lithophile elements (LILE) relative to high field strength elements (HFSE). As well they show a slightly negative Eu anomaly (Eu/Eu* = 0.72 – 0.97). The whole-rock geochemistry of the studied rocks suggests that they are related to each other by fractional crystallization. LA-MC-ICP-MS U-Pb analyses in zircon grains from two volcanic rock samples (GCH-119 and GCH-171) gave ages ranging of 5.47 ± 0.22 Ma to 2.44 ± 0.79 Ma, which corresponds to the Pliocene period. In four samples analysed for Sr and Nd isotopes 87Sr/86Sr ratios range from 0.704082 to 0.705931 and εNd values vary between +3.34 and +5. These values could be regarded to as representing mantle derived magmas. Taking into account the comparing rare earth element (REE) patterns, an origin of the parental magmas in enriched lithospheric mantle is suggested. Finally, it is concluded that Pliocene Gandab volcanic rocks are related to the post-collision environment that followed the Neo-Tethys subduction

Optimization of bone tissue scaffolds fabricated by robocasting technique

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record 11th World congress on structural and multidisciplinary optimization (WCSMO-11), 7–12 June 2015, Sydney, AustraliaWhile excellent biological and mechanical properties of ceramic scaffolds place them amongst the main candidates for applications of bone and cartilage repair, an optimum trade-off between critical biological and mechanical functions remains challenging during design process. These ceramic scaffolds should not only enhance tissue regeneration function, but also be of adequate mechanical strength particularly in load-bearing applications. One of the techniques used for the fabrication of ceramic scaffolds is robocating which has so far received little attention in the currently available optimization analyses related to the design of these scaffolds. In this study a vigorous optimization analysis based on finite element (FE) method is performed to maximize compressive strengths of such scaffolds while maintaining the minimum biological functions required for tissue ingrowth. The results demonstrate that an optimized functionality of ceramic scaffolds fabricated by robocasting needs a careful design of critical geometrical features

Anticancer activity of curcumin on human breast adenocarcinoma: Role of Mcl-1 gene

Background: Breast cancer is the second leading cause of cancer-related death among females in the world. To date, chemotherapy has been the most frequently used treatment for breast cancer and other cancers. However, some natural products have been used, as alternative treatments for cancers including breast cancer, due to their wide range of biological activities and low toxicity in animal models. Objectives: The present study examined the anti-proliferative activity of curcumin and its effect(s) on the apoptosis of breast cancer cells. Materials and Methods: This study was performed by an in vitro assay and the anticancer effects of curcumin were determined by MTT (3-4,5-dimethylthiazol-2-yl-2,5 diphenyl tetrazolium bromide). We used quantitative real time Polymerase Chain Reaction (PCR) for detection of Mcl-1 gene expression in treated groups and then compared them to control samples. Results: In the treatment group, there were higher levels of cell death changes than the control group. The results also showed that the Mcl-1 gene expression declined in the tested group as compared to the control group. Conclusions: Our present findings indicated that curcumin significantly inhibited the growth of human breast cancer cell MCF-7 by inducing apoptosis in a dose- and time- dependent manner, accompanied by a decrease in MCF-7 cell viability. Furthermore, our results showed that quantitative real-time PCR could be used as a direct method for detection Mcl-1 gene expression in tested samples and normal samples. © 2015, Iranian Journal of Cancer Prevention

VALUATION OF GROUNDWATER EXPLOITATION OF AGRICULTURAL CASE STUDY OF WHEAT FARMERS IN KHATAM CITY

Country with an annual average rainfall of 250 mm is faced with the problem of dehydration and non-uniform distribution of water resources. Scarcity of water on the one hand, and the enormous costs on the other hand, is considered productivity and economic value of water as one of the most important national goal. Consumption of Water in agricultural sector includes about 90 percent of the country´s water consumption, so the economic value of water in agriculture is one of the most important priorities in water resources management. In this study the economic value of water by considering methods of calculate, methods based on basic function of social welfare witch economic value of water for production of Wheat in Yazd (Heart - khatam) was analyzed required data and information is collected from 100 questionnaires using two-stage cluster sampling in 1387. For estimation of functions is used from Eviews5 software. The results show decreasing scale in the region. Also marginal production of factors so that water, labor and pesticides evaluated respectively 1.4, 65 and 1113 kg per unit. Producers are willing to sacrifice to 0.228 unit of labor (or sacrifice to 0.0067 unit of pesticides). Marginal production-factor price ration for water, labor and pesticides are 0.0049, 0.0005 and 0.0159 respectively. Actual results (economic) value of water is 12,593 Rials witch difference significantly with current value (277.4 Rials) in region that leading to excessive withdrawal of groundwater water in region. The shadow price of labor and pesticides are 604,500 and 10,350,900 Rials respectively. Price and income elasticity of water derived demand are 15.33 and 45.329 respectively. JEL Classifications : C13, C20, D21, Q11, Q25, Q34. Key words: Cobb Douglas production function, economic value, efficiency to scale, demand elasticity, Yazd province, Khatam-Hear

On the assessment of non-metallic inclusions by part 13 of API 579 -1/ASME FFS-1 2016

Improvement of nondestructive inspection techniques has allowed more frequent detection of closely spaced zones of non-metallic inclusions in pressure vessels made of low carbon steel. In the present study, closely spaced inclusions in an in-service cylindrical horizontal pressure vessel were detected by Scan-C ultrasonic inspection and considered as laminations to be assessed by Part 13 of the API 579-1/ASME FFS-1 2016 standard. The outcoming results were considered as a rejection for Level 1 assessment, and a repair or replacement of the component was required, even though it retained a significant remaining strength. Thus, an alternative procedure to assess the mechanical integrity of pressure vessels containing zones of non-metallic inclusions is proposed by adopting some criteria of the API 579-1/ASME FFS-1 Part 13 standard procedure and taking into consideration the dimensions and grouping characteristics of the inclusion zones.&nbsp; &nbsp; &nbsp

A modular design strategy to integrate mechanotransduction concepts in scaffold-based bone tissue engineering

Repair or regeneration of load-bearing bones has long been an incentive for the tissue engineering community to develop a plethora of synthetic bone scaffolds. Despite the key role of physical forces and the mechanical environment in bone regeneration, the mechanotransduction concept has rarely been incorporated in structural design of bone tissue scaffolds, particularly those made of bioactive materials such as hydrogels and bioceramics. Herein, we introduce a modular design strategy to fabricate a load bearing device that can support a wide range of hydrogel- and ceramic-based scaffolds against complex in-vivo loading conditions to induce desirable mechanical strains for bone regeneration within the scaffolds. The device is comprised of a fenestrated polymeric shell and ceramic structural pillars arranged in a sophisticated configuration to provide ample internal space for the scaffold, also enabling it to purposely regulate the levels of strains and stresses within the scaffolds. Utilizing this top-down design approach, we demonstrate that the failure load of alginate hydrogels increases 3200-fold in compression, 300-fold in shear and 75-fold in impact, achieving the values that enable them to withstand physiological loads in weight-bearing sites, while allowing generation of osteoinductive strains (i.e., 0.2-0.4%) in the hydrogel. This modular design approach opens a broad range of opportunities to utilize various bioactive but mechanically weak scaffolds for the treatment of load-bearing defects and exploiting mechanobiology strategies to improve bone regeneration

Anti-proliferative and apoptotic effects of aqueous extract of ziziphus jujube in human thyroid carcinoma cell lines (C643)

Background: Ziziphus jujuba, which is known as �Annab� or �Onnab� in Iran, is an effective compound against some cancer cell lines. The present study aimed to investigate the anti-mutagenic and anticancer effects of the aqueous extract of Z. jujuba on C643 human thyroid carcinoma cells. Methods: C643 cells were cultured in (Roswell Park memorial institute) RPMI 1640 medium (Sigma) supplemented with 10 fetal bovine serum (FBS), penicillin-streptomycin, and L-glutamine. After incubating the cultures at 37ºC with 5 CO2, MTT assay was used to determine the inhibitory effect of Z. jujuba on cell proliferation. Cell cycle progression was monitored by sub-G1 apoptosis assay using flow cytometry. Finally, anti-mutagenicity properties of the extract were evaluated using a standard reverse mutation assay (Ames test), which was performed with a histidine auxotroph strain of Salmonella typhimurium (TA100) and exposure to a carcinogenic substance (sodium azide). Results: The aqueous extract of Z. jujuba inhibited the growth of C643 cells in a concentration range of 0.5-2 mg/mL and exhibited cytotoxic effects on C643 cells in a concentration-dependent manner (IC50: 1.671 mg/mL). The mechanism of action was the induction of apoptosis in the cells. The results of Ames test indicated a significant difference in the anti-mutagenic effects of Z. jujuba aqueous extract and controls (distilled water and sodium azide) (1.671 mg/mL) (P &lt; 0.01). In addition, the herbal extract prevented reverted mutations and the hindrance percent was 87.97. Conclusions: According to the results, the aqueous extract of Z. jujuba fruit exerted anti-proliferative and apoptotic effects on C643 thyroid carcinoma cell lines and may be potentially useful as an anticancer agent. © 2018, Author(s)

Review of Current Developments on High Strength Pipeline Steels for HIC Inducing Service

Nowadays, an increasing number of oil and gas transmission pipes are constructed with high-strength low alloy steels (HSLA); however, many of these pipelines suffer from different types of hydrogen damages, such as hydrogen-induced cracking (HIC). So many research efforts are being carried out to reduce the detrimental effects of hydrogen damage in HSLA steel pipes. The thermomechanical control process (TMCP) is a microstructural control technique that is able to eliminate the conventional heat treatment after hot rolling. Recent research demonstrated that TMCP provides high HIC resistance without adding high amounts of alloying elements or expensive heat treatments. However, once these HSLA steel pipes are put into service, they experience HIC damage, and the prediction of its kinetics is a necessary condition to perform Fitness-For-Service assessments. To develop a reliable predictive model for the kinetics of HIC, the relations among the microstructural features, environmental parameters, and mechanical properties have to be fully understood. This paper presents a review of the key metallurgical and processing factors to develop HSLA steel pipes, as well as a review of the phenomenological and empirical models of HIC kinetics in order to identify specific research directions for further investigations aimed to establish a reliable and sound model of HIC kinetics. &nbsp