Control of Cell Cycle Progression by mTOR

Over the past few years it has become apparent that cancer cells require the activation of a set of intra-cellular signals that promote cell cycle progression and survival. One of the most common survival signals activated in human cancers is mediated by mTOR -the mammalian target of rapamycin. mTOR is a critical nutrient and energy sensor in cells that lets the cell know that there is sufficient material available for a cell to double its mass and divide. mTOR causes the phosphorylation of downstream targets ribosomal subunit S6 kinase and eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4E-BP1), which promotes cell cycle progression. mTOR suppresses the activity of the tumor suppressor Transforming Growth Factor-β (TGF-β). TGF-β plays a central role in causing G1 cell cycle arrest. Rapamycin is a highly specific allosteric inhibitor of mTOR. In the presence of serum, rapamycin activates TGF- β signaling and causes G1 cell cycle arrest. This is one reason why rapamycin is frequently called a \u27cytostatic drug\u27. While conventional low (nM) doses of rapamycin can retard G1 cell cycle progression, our lab has recently found that high (μ) doses of rapamycin are needed to induce complete G1 cell cycle arrest. However, it is unclear as to what causes the cells to be sensitive to high dose rapamycin treatment with regard to G1 cell cycle progression. Prior studies in lab has shown that rapamycin in absence of serum induces apoptosis. High dose rapamycin inhibits eIF4E. In this study we revealed that knockdown of eIF4E causes apoptosis both in the presence and absence of serum. This was unexpected because rapamycin induces G1 cell cycle arrest in the presence of serum. Upon investigation, we have found that inactivated S6 kinase prevents the apoptotic effect observed by singular knockdown of eIF4E and results in G1 cell cycle arrest. This effect is dependent on TGF-β signaling which contributes to G1 cell cycle arrest. Suppression of S6 kinase phosphorylation alone is insufficient to cause complete cell cycle arrest, indicating that complete G1 cell cycle arrest is due to suppression of both S6 kinase and eIF4E. This proves that the cytostatic effect of rapamycin is suppression of both S6 kinase and eIF4E, while the cytotoxic effects are due suppression of eIF4E in the absence of S6 kinase-dependent activation of TGF-β signals. This study also shows that nano-molar doses that inhibit S6 kinase were sufficient to activate TGF-β signaling. The high doses of rapamycin used to inhibit eIF4E correlated with inhibition of Rb phosphorylation. Consistent with these observations, knockdown of both Smad4 (an important player of TGF-β signaling) and Rb reversed the cytostatic effects of rapamycin. These data indicate that the G1 cell cycle arrest induced by rapamycin is due to the up regulation of TGF-β signaling and down-regulation of Rb phosphorylation via phosphorylation of the mTORC1 substrates S6 kinase and 4E-BP1 respectively. Altogether, our findings not only place an importance to the evaluation of the activity/expression level of S6 kinase and eIF4E as readouts for rapamycin efficacy but also enhance the current understanding of the cytostatic effects of mTORC1 suppression with therapeutic implications

Translation Of AADL To PNML To Ensure The Utilization Of Petri Nets

Architecture Analysis and Design Language (AADL), which is used to design and analyze software and hardware architectures of embedded and real-time systems, has proven to be a very efficient way of expressing the non-functional properties of safety-critical systems and architectural modeling. Petri nets are the graphical and mathematical modeling tools used to describe and study information processing systems characterized as concurrent and distributed. As AADL lacks the formal semantics needed to show the functional properties of such systems, the objective of this research was to extend AADL to enable other Petri nets to be incorporated into Petri Net Markup Language (PNML), an interchange language for Petri nets. PNML makes it possible to incorporate different types of analysis using different types of Petri net. To this end, the interchange format Extensible Markup Language (XML) was selected and AADL converted to AADL-XML (the XML format of AADL) and Petri nets to PNML, the XML-format of Petri nets, via XSLT script. PNML was chosen as the transfer format for Petri nets due to its universality, which enables designers to easily map PNML to many different types of Petri nets. Manual conversion of AADL to PNML is error-prone and tedious and thus requires automation, so XSLT script was utilized for the conversion of the two languages in their XML format. Mapping rules were defined for the conversion from AADL to PNML and the translation to XSLT automated. Finally, a PNML plug-in was designed and incorporated into the Open Source AADL Tool Environment (OSATE)

Mapping AADL to Petri Net Tool-Sets Using PNML Framework

Architecture Analysis and Design Language (AADL) has been utilized to specify and verify non- functional properties of Real-Time Embedded Systems (RTES) used in critical application systems. Examples of such critical application systems include medical devices, nuclear power plants, aer- ospace, financial, etc. Using AADL, an engineer is enable to analyze the quality of a system. For example, a developer can perform performance analysis such as end-to-end flow analysis to guarantee that system components have the required resources to meet the timing requirements relevant to their communications. The critical issue related to developing and deploying safety critical systems is how to validate the expected level of quality (e.g., safety, performance, security) and functionalities (capabilities) at design level. Currently, the core AADL is extensively applied to analyze and verify quality of RTES embed in the safety critical applications. The notation lacks the formal semantics needed to reason about the logical properties (e.g., deadlock, livelock, etc.) and capabilities of safety critical systems. The objective of this research is to augment AADL with exit- ing formal semantics and supporting tools in a manner that these properties can be automatically verified. Toward this goal, we exploit Petri Net Markup Language (PNML), which is a standard act- ing as the intermediate language between different classes of Petri Nets. Using PNML, we interface AADL with different classes of Petri nets, which support different types of tools and reasoning. The justification for using PNML is that the framework provides a context in which interoperability and exchangeability among different models of a system specified by different types of Petri nets is possible. The contributions of our work include a set of mappings and mapping rules between AADL and PNML. To show the feasibility of our approach, a fragment of RT-Embedded system, namely, Cruise Control System has been used

Cultural Crisis, Deteriorating Heritage, and Placemaking: A Study of Rural West Bengal, India

‘Culture’ denotes the co-shared beliefs, values, ethos, norms, lifeworlds, and activities commonly represent nature-culture reciprocity. In several remote areas of India, folk culture still breaths within its age-old life world. Against this backdrop, the southwestern part of West Bengal, also known as ‘Jangal Mahal’ has been studied in the present research. In this area, approximately 40% of the population directly depends on indigenous sources of livelihood, and they belong to tribal communities like Mahato, Kurmi, Lodha, Santal, Bauri, and others. These native people are culturally distinct and are identified through their folksongs and dance forms, such as Tusu, Kirtan, Baul, Bhadu, and folk dances, such as Chhau, Khati, etc. However, urban spaces and citizens’ choices for entertainment have brought about considerable changes in the culture and life of these people. Resultantly, with the increasing pace, deterioration in the heritage and culture of such groups seems to set in. Thus, this study highlights the changing scenarios of cultural crises, deteriorating heritage values, and placemaking. We have followed participatory methods, including field observation, interviews and group discussions. And a door-to-door survey was conducted in the 12 villages of four districts with a semi-structured survey schedule. Sixty troupes were selected for interview and Focused Group Discussions (FGDs). The findings show that values and cultural practices change over time, thereby losing their identity. The placemaking of popular culture results in a deep crisis in livelihood and lifestyle. People are slowly adopting other modes of earning, which further threaten their culture. This study aims to suggest suitable ameliorative measures to preserve the pristine cultural art forms and safeguard livelihood and skill sets

Consumeras Acceptance towards Genetically Modified Crops and Growth of the Economy: A Theoretical Approach

This paper develops a three-sector theoretical growth model to capture the role of consumers acceptance towards the second generation of genetically modified GM crops in the long run growth process of the economy An Acceptance towards GM crop parameter is defined as a ratio of consumption of GM to traditional variety of food whose growth rate is determined by growth rate of human capital Dynamic stability of the system is ensured provided the value of acceptance parameter is within a certain range A range of the acceptance parameter is also obtained which ensures not only the dynamic stability of the system but also ensures higher rate of growth of an economy that produces both GM and non-GM crops compared to an economy that does not produce GM crops The empirical validation of the model through panel data analysis suggests that research and development activity in agriculture is key to the growth process of the economy as it helps to form acceptance towards new technology among consumer

Ruling out Strongly Interacting Dark Matter-Dark Radiation Models from Joint Cosmic Microwave Background-Quasar Observations

The cold dark matter (CDM) paradigm provides a remarkably good description of the Universe's large-scale structure. However, some discrepancies exist between its predictions and observations at very small sub-galactic scales. To address these issues, the consideration of a strong interaction between dark matter particles and dark radiation emerges as an intriguing alternative. In this study, we explore the constraints on those models using joint observations of Cosmic Microwave Background (CMB) and Quasars with our previously built parameter estimation package CosmoReionMC. At 2-$\sigma$ confidence limits, this analysis rules out all strongly interacting Dark Matter - Dark Radiation models proposed to date, representing the most stringent constraint on those models to the best of our knowledge. Future research using a 21-cm experiment holds the potential to reveal stronger constraints or uncover hidden interactions within the dark sector.Comment: Submitted to MNRAS Letter

Primary completion rates across socio-religious communities in West Bengal

Primary completion rates of Muslims in West Bengal are substantially lower than that of upper caste communities as well as backward castes, scheduled castes and tribes. Further, analysis of age-specific pcr indicates that differences in pcr between Muslims and other communities may have actually increased in recent years. An econometric analysis reveals that age, gender, household size and expenditure levels, education and gender of decision-maker, etc, are important determinants of these differences in pcr. But use of Census data and District Information System for Education statistics indicates that deficiencies in infrastructural facilities in Muslim-concentrated districts also have a significant role in the low pcrs of Muslim children

Primary completion rates across socio-religious communities in West Bengal

Primary completion rates of Muslims in West Bengal are substantially lower than that of upper caste communities as well as backward castes, scheduled castes and tribes. Further, analysis of age-specific pcr indicates that differences in pcr between Muslims and other communities may have actually increased in recent years. An econometric analysis reveals that age, gender, household size and expenditure levels, education and gender of decision-maker, etc, are important determinants of these differences in pcr. But use of Census data and District Information System for Education statistics indicates that deficiencies in infrastructural facilities in Muslim-concentrated districts also have a significant role in the low pcrs of Muslim children

Peepli [Live]: A Social Satire on Contemporary India

Films may be regarded as a powerful medium of expression that convey information on the history, civilization, philosophy, politics, education and religion of a given culture. Over decades, societal and environmental factors have been a major source of creative inspiration for filmmakers in India. Accordingly, contemporary Indian films have incorporated themes relevant to today’s times such as individual conflicts, societal hierarchy, corrupt bureaucracy, commercialization of religion, politics, educational systems, mental disorders, and terrorism among others. A powerful example of this is obtained in the film Peepli [Live] (2010) which is believed to have been produced as a response to a spate of farmer suicides that took place in India since the 1990s. It is the story of a farmer who considers committing suicide so that his family can benefit from the compensation offered by the government. The film also raises other related issues such as the general apathy of political leaders and the insensitivity of the media towards impoverished farmers. Peepli [Live] uses black humor to introduce these issues and leaves the audience with pertinent questions about current socio-political systems and the uncertainties about the nation’s future. Accordingly, the present study is devoted towards examining Peepli [Live] which remains significantly under-researched by scholars of Indian cinema. This thesis focuses on the description of three themes that have been presented in the film, namely, black humor, media and sensationalism; and gender subversion. This is achieved by drawing attention to particular elements in the film such as the background, storyline, characters,and conflicts. It is expected that this will help understand how the film was successful in highlighting rural India’s lived reality and why it has garnered tremendous national and international acclaim

Blocking anaplerotic entry of glutamine to TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs

Cancer cells undergo a metabolic transformation that allows for increased anabolic demands wherein glycolytic and TCA cycle intermediates are shunted away for the synthesis of biological molecules required for cell growth and division. One of the key shunts is the exit of citrate from the mitochondria and the TCA cycle for the generation of cytosolic acetyl-CoA that can be used for fatty acid and cholesterol biosynthesis. With the loss of mitochondrial citrate, cancer cells rely on the “conditionally essential” amino acid glutamine (Q) as an anaplerotic carbon source for TCA cycle intermediates. While Q deprivation causes G1 cell cycle arrest in non-transformed cells, its impact on the cancer cell cycle is not well characterized. We report here a correlation between bypass of the Q-dependent G1 checkpoint and cancer cells harboring K-Ras mutations. Instead of arresting in G1 in response to Q-deprivation, K-Ras driven cancer cells arrest in either S- or G2/M-phase. Inhibition of K-Ras effector pathways was able to revert cells to G1 arrest upon Q deprivation. Blocking anaplerotic utilization of Q mimicked Q deprivation – causing S- and G2/M-phase arrest in K-Ras mutant cancer cells. Significantly, Q deprivation or suppression of anaplerotic Q utilization created synthetic lethality to the cell cycle phase-specific cytotoxic drugs, capecitabine and paclitaxel. These data suggest that disabling of the G1 Q checkpoint could represent a novel vulnerability of cancer cells harboring K-Ras and possibly other mutations that disable the Q-dependent checkpoint