MTOR function and therapeutic targeting in breast cancer

The mTOR pathway was discovered in the late 1970s after the compound and natural inhibitor of mTOR, rapamycin was isolated from the bacterium Streptomyces hygroscopicus. mTOR is serine/threonine kinase belonging to the phosphoinositide 3-kinase related kinase (PIKK) family. It forms two distinct complexes; mTORC1 and mTORC2. mTORC1 has a key role in regulating protein synthesis and autophagy whilst mTORC2 is involved in regulating kinases of the AGC family. mTOR signaling is often over active in multiple cancer types including breast cancer. This can involve mutations in mTOR itself but more commonly, in breast cancer, this is related to an increase in activity of ErbB family receptors or alterations and mutations of PI3K signaling. Rapamycin and its analogues (rapalogues) bind to the intercellular receptor FKBP12, and then predominantly inhibit mTORC1 signaling via an allosteric mechanism. Research has shown that inhibition of mTOR is a useful strategy in tackling cancers, with it acting to slow tumor growth and limit the spread of a cancer. Rapalogues have now made their way into the clinic with the rapalogue everolimus (RAD-001/Afinitor) approved for use in conjunction with exemestane, in post-menopausal breast cancer patients with advanced disease who are HER-2 negative (normal expression), hormone receptor positive and whose prior treatment with non-steroidal aromatase inhibitors has failed. Testing across multiple trials has proven that everolimus and other rapalogues are a viable way of treating certain types of cancer. However, rapalogues have shown some drawbacks both in research and clinically, with their use often activating feedback pathways that counter their usefulness. As such, new types of inhibitors are being explored that work via different mechanisms, including inhibitors that are ATP competitive with mTOR and which act to perturb signaling from both mTOR complexes.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385631

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

The 18-kDa TSPO (translocator protein) localizes on the outer mitochondrial membrane (OMM) and participates in cholesterol transport. Here, we report that TSPO inhibits mitochondrial autophagy downstream of the PINK1-PARK2 pathway, preventing essential ubiquitination of proteins. TSPO abolishes mitochondrial relocation of SQSTM1/p62 (sequestosome 1), and consequently that of the autophagic marker LC3 (microtubule-associated protein 1 light chain 3), thus leading to an accumulation of dysfunctional mitochondria, altering the appearance of the network. Independent of cholesterol regulation, the modulation of mitophagy by TSPO is instead dependent on VDAC1 (voltage-dependent anion channel 1), to which TSPO binds, reducing mitochondrial coupling and promoting an overproduction of reactive oxygen species (ROS) that counteracts PARK2-mediated ubiquitination of proteins. These data identify TSPO as a novel element in the regulation of mitochondrial quality control by autophagy, and demonstrate the importance for cell homeostasis of its expression ratio with VDAC1

Experimental Determination of Optimal Conditions for Reactive Coupling of Biodiesel Production With in situ Glycerol Carbonate Formation in a Triglyceride Transesterification Process

This study investigated a reactive coupling to determine the optimal conditions for transesterification of rapeseed oil (RSO) to fatty acid methyl ester (FAME) and glycerol carbonate (GLC) in a one-step process, and at operating conditions which are compatible with current biodiesel industry. The reactive coupling process was studied by transesterification of RSO with various molar ratios of both methanol and dimethyl carbonate (DMC), using triazabicyclodecene (TBD) guanidine catalyst and reaction temperatures of 50–80°C. The optimal reaction conditions obtained, using a Design of Experiments approach, were a 2:1 methanol-to-RSO molar ratio and 3:1 DMC-to-RSO molar ratio at 60°C. The FAME and GLC conversions at the optimal conditions were 98.0 ± 1.5 and 90.1 ± 2.2%, respectively, after 1 h reaction time using the TBD guanidine catalyst. Increase in the DMC-to-RSO molar ratio from 3:1 to 6:1 slightly improved the GLC conversion to 94.1 ± 2.8% after 2 h, but this did not enhance the FAME conversion. Methanol substantially improved both FAME and GLC conversions at 1:1–2:1 methanol-to-RSO molar ratios and enhanced the GLC separation from the reaction mixture. It was observed that higher methanol molar ratios (>3:1) enhanced only FAME yields and resulted in lower GLC conversions due to reaction equilibrium limitations. At a 6:1 methanol-to-RSO molar ratio, 98.4% FAME and 73.3% GLC yields were obtained at 3:1 DMC-to-RSO molar ratio and 60°C. This study demonstrates that formation of low value crude glycerol can be reduced by over 90% compared to conventional biodiesel production, with significant conversion to GLC, a far more valuable product

The biosocial event : responding to innovation in the life sciences

Innovation in the life sciences calls for reflection on how sociologies separate and relate life processes and social processes. To this end we introduce the concept of the ‘biosocial event’. Some life processes and social processes have more mutual relevance than others. Some of these relationships are more negotiable than others. We show that levels of relevance and negotiability are not static but can change within existing relationships. Such changes, or biosocial events, lie at the heart of much unplanned biosocial novelty and much deliberate innovation. We illustrate and explore the concept through two examples – meningitis infection and epidemic, and the use of sonic ‘teen deterrents’ in urban settings. We then consider its value in developing sociological practice oriented to critically constructive engagement with innovation in the life sciences

Anomaly Equations and Intersection Theory

Six-dimensional supergravity theories with N=(1,0) supersymmetry must satisfy anomaly equations. These equations come from demanding the cancellation of gravitational, gauge and mixed anomalies. The anomaly equations have implications for the geometrical data of Calabi-Yau threefolds, since F-theory compactified on an elliptically fibered Calabi-Yau threefold with a section generates a consistent six-dimensional N=(1,0) supergravity theory. In this paper, we show that the anomaly equations can be summarized by three intersection theory identities. In the process we also identify the geometric counterpart of the anomaly coefficients---in particular, those of the abelian gauge groups---that govern the low-energy dynamics of the theory. We discuss the results in the context of investigating string universality in six dimensions.Comment: 29 pages + appendices, 8 figures; v2: minor corrections, references added; v3: minor corrections, reference adde

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Vulnerability of low-arsenic aquifers to municipal pumping in Bangladesh

Sandy aquifers deposited >12,000 years ago, some as shallow as 30 m, have provided a reliable supply of low-arsenic (As) drinking water in rural Bangladesh. This study concerns the potential risk of contaminating these aquifers in areas surrounding the city of Dhaka where hydraulic heads in aquifers >150 m deep have dropped by 70 m in a few decades due to municipal pumping. Water levels measured continuously from 2012 to 2014 in 12 deep (>150 m), 3 intermediate (90-150 m) and 6 shallow (<90 m) community wells, 1 shallow private well, and 1 river piezometer show that the resulting drawdown cone extends 15-35 km east of Dhaka. Water levels in 4 low-As community wells within the 62-147 m depth range closest to Dhaka were inaccessible by suction for up to a third of the year. Lateral hydraulic gradients in the deep aquifer system ranged from 1.7 × 10-4 to 3.7 × 10-4 indicating flow towards Dhaka throughout 2012-2014. Vertical recharge on the edge of the drawdown cone was estimated at 0.21 ± 0.06 m/yr. The data suggest that continued municipal pumping in Dhaka could eventually contaminate some relatively shallow community wells

Smc5/6: a link between DNA repair and unidirectional replication?

Of the three structural maintenance of chromosome (SMC) complexes, two directly regulate chromosome dynamics. The third, Smc5/6, functions mainly in homologous recombination and in completing DNA replication. The literature suggests that Smc5/6 coordinates DNA repair, in part through post-translational modification of uncharacterized target proteins that can dictate their subcellular localization, and that Smc5/6 also functions to establish DNA-damage-dependent cohesion. A nucleolar-specific Smc5/6 function has been proposed because Smc5/6 yeast mutants display penetrant phenotypes of ribosomal DNA (rDNA) instability. rDNA repeats are replicated unidirectionally. Here, we propose that unidirectional replication, combined with global Smc5/6 functions, can explain the apparent rDNA specificity

Positive Association between Aspirin-Intolerant Asthma and Genetic Polymorphisms of FSIP1: a Case-Case Study

<p>Abstract</p> <p>Background</p> <p>Aspirin-intolerant asthma (AIA), which is caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, causes lung inflammation and reversal bronchi reduction, leading to difficulty in breathing. Aspirin is known to affect various parts inside human body, ranging from lung to spermatogenesis. <it>FSIP1</it>, also known as <it>HDS10</it>, is a recently discovered gene that encodes fibrous sheath interacting protein 1, and is regulated by amyloid beta precursor protein (APP). Recently, it has been reported that a peptide derived from APP is cleaved by α disintegrin and metalloproteinase 33 (<it>ADAM33</it>), which is an asthma susceptibility gene. It has also been known that the <it>FSIP1 </it>gene is expressed in airway epithelium.</p> <p>Objectives</p> <p>Aim of this study is to find out whether <it>FSIP1 </it>polymorphisms affect the onset of AIA in Korean population, since it is known that AIA is genetically affected by various genes.</p> <p>Methods</p> <p>We conducted association study between 66 single nucleotide polymorphisms (SNPs) of the <it>FSIP1 </it>gene and AIA in total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of <it>FSIP1 </it>and AIA were analyzed with sex, smoking status, atopy, and body mass index (BMI) as covariates.</p> <p>Results</p> <p>Initially, 18 SNPs and 4 haplotypes showed associations with AIA. However, after correcting the data for multiple testing, only one SNP showed an association with AIA (corrected <it>P</it>-value = 0.03, OR = 1.63, 95% CI = 1.23-2.16), showing increased susceptibility to AIA compared with that of ATA cases. Our findings suggest that <it>FSIP1 </it>gene might be a susceptibility gene for aspirin intolerance in asthmatics.</p> <p>Conclusion</p> <p>Although our findings did not suggest that SNPs of <it>FSIP1 </it>had an effect on the reversibility of lung function abnormalities in AIA patients, they did show significant evidence of association between the variants in <it>FSIP1 </it>and AIA occurrence among asthmatics in a Korean population.</p