A miR-200c/141-BMI1 autoregulatory loop regulates oncogenic activity of BMI1 in cancer cells.

MicroRNAs (miRNAs) are known to function as oncomiRs or tumor suppressors and are important noncoding RNA regulators of oncogenesis. The miR-200c/141 locus on chromosome 12 encodes miR-200c and miR-141, two members of the miR-200 family, which have been shown to function as tumor suppressive miRNAs by targeting multiple oncogenic factors such as polycomb group protein BMI1. Here, we show that BMI1 reciprocally functions as a transcriptional repressor of the miR-200c/141 cluster and that BMI1 inhibitors upregulate expression of miR-200c and miR-141. Our data suggest that BMI1 binds to the miR-200c/141 promoter and regulates it through transcription factor binding motifs E-box 2 and Z-box 1 to repress expression of miR-200c/141 cluster. We also show that PTC-209, a small molecule inhibitor of BMI1 gene expression induces cellular senescence and transcriptionally upregulates expression of miR-200c/141 cluster in breast cancer cells. Furthermore, inhibition of expression of miR-200c or miR-141 overcomes tumor suppressive effects of PTC-209 including induction of cellular senescence and downregulation of breast cancer stem cell phenotype. Therefore, our studies suggest a reciprocal regulation between BMI1 and miR-200c/141 cluster, and that BMI1 inhibitory drugs can further amplify their inhibitory effects on BMI1 via multiple mechanisms including posttranscriptional regulation by upregulating BMI1 targeting miRNAs

Oxidative stress, cellular senescence and ageing

Almost a half century ago, the free radical theory of ageing proposed that the reactive oxygen species (ROS) is a key component which contributes to the pathophysiology of ageing in mammalian cells. Over the years, numerous studies have documented the role of oxidative stress caused by ROS in the ageing process of higher organisms. In particular, several age-associated disease models suggest that ROS and oxidative stress modulate the incidence of age-related pathologies, and that it can strongly influence the ageing process and possibly lifespan. The exact mechanism of ROS and oxidative stress-induced age-related pathologies is not yet very clear. Damage to biological macromolecules caused by ROS is thought to result in many age-related chronic diseases. At the cellular level, increased ROS leads to cellular senescence among other cellular fates including apoptosis, necrosis and autophagy. Cellular senescence is a stable growth arrest phase of cells characterized by the secretion of senescence-associated secretory phenotype (SASP) factors. Recent evidence suggests that cellular senescence via its growth arrest phenotype and SASP factors is a strong contributing factor in the development of age-associated diseases. In addition, we suggest that SASP factors play an important role in the maintenance of age-associated pathologies via a positive feedback mechanism. This review aims to provide an overview of ROS mechanics and its possible role in the ageing process via induction of cellular senescence

A positive feedback loop regulates the expression of polycomb group protein BMI1 via WNT signaling pathway

Polycomb group protein BMI1 plays an important role in cellular homeostasis by maintaining a balance between proliferation and senescence. It is often overexpressed in cancer cells and is required for self-renewal of stem cells. At present, very little is known about the signaling pathways that regulate the expression of BMI1. Here, we report that BMI1 autoactivates its own promoter via an E-box present in its promoter. We show that BMI1 acts as an activator of the WNT pathway by repressing Dickkopf (DKK) family of WNT inhibitors. BMI1 mediated repression of DKK proteins; in particular, DKK1 led to up-regulation of WNT target c-Myc, which in turn further led to transcriptional autoactivation ofBMI1. Thus, a positive feedback loop connected by the WNT signaling pathway regulates BMI1 expression. This positive feedback loop regulating BMI1 expression may be relevant to the role of BMI1 in promoting cancer and maintaining stem cell phenotype

Non Ennarabile Textum: Allusive Ekphrasis in Francisco Javier Alegre\u27s Alexandrias

Neo-Latin literature in colonial New Spain has a rich history that has only in recent years garnered broader interest from scholars. One of the most unique works produced in New Spain during this time is Jesuit scholar Francisco Javier Alegre’s Alexandrias, an epic that depicts Alexander the Great’s conquest of the Phoenician city of Tyre. As there is scant scholarship analyzing the literary elements of the Alexandrias, this paper focuses only on Alegre’s usage of ekphrasis—a detailed description of an object—in book one of the epic, rather than attempting to explore every allusive aspect in this dense text. Th rough allusive ekphrasis, Alegre elegantly incorporates the work of ancient poets such as Ovid not only to highlight his own ability as a poet, but also to subtly address topics that would otherwise be inappropriate for a Jesuit priest to write about. In addition to this more noticeable usage of allusion, Alegre’s specific manipulation of poetic language in this scene also reveals a potential reading of Alexander the Great as a historical analogue to Hernan Cortés, both of whom gained fame through conquest. Analysis of this text—even through an allusive lens alone—reveals the intricacy with which Alegre and his contemporaries were composing their works, and emphasizes the value of deeper investigations into Neo-Latin literature

The Impact of Sales Promotion Schemes on Mobile Phone Services: A Comparative Analysis of Prepaid and Postpaid Mobile Users in Dehradun

India's telecommunications business has significantly grown in the modern era of the information society. India's demand for mobile services has seen a spectacular increase, which has sparked fierce competition among various providers of telecommunications services. These companies provide a variety of promotional plans to encourage clients. In order to make educated decisions in this dynamic sector, it has become essential to comprehend consumer preferences and behavior. This study intends to evaluate consumer attitudes of several Dehradun-based mobile phone service providers, with a particular emphasis on their pricing policies and levels of satisfaction with their services. It also aims to predict how mobile phone services will affect socioeconomic developments in the future. To accomplish these goals, 150 mobile users from the city in Dehradun were randomly chosen as a sample. The results show that respondents preferred prepaid cell services over postpaid ones. The study also shows a significant relationship among respondents' monthly income and educational background and the marketing techniques they selected

Flow Maximization Problem as Linear Programming Problem with Capacity Constraints

Flow maximization is a fundamental problem in mathematics; there are several algorithms available to solve this problem, but these algorithms have some limitations. This paper presents the flow maximization problem as a Linear Programming Problem (L.P.P.). The solution given by L.P.P. formulation of the problem and provided by Ford Fulkerson algorithm is same. This paper also compares the single path flow and k-splitting of the flow and suggests that k-splitting of flow is better than single path flow

pRb or its cousins: Who controls the family business?

Comment on: Bazarov A, et al. Cell Cycle 2012; 11:1008–101

Recovery Ventilation and Oxygen Debt-A Mathematical Model for the Prediction of Recovery Ventilation

A Mathematical model has been evolved for the estimation of recovery ventilation following an exercise. The model has been used to estimate recovery ventilation in moderate to heavy exercise for a period of 32 minutes. The model gives satisfactory predictions for persons of different age groups and under different environment conditions thus establishing its universal applicability

Snowfall Statistics of Some SASE Field Stations in J&K

North-west Himalayan region comprises five mountain ranges. Their orientation and complexterrain influence the weather over the region. Sudden altitudinal changes also affect the weathersystems to a considerable extent . Due to the prevailing in homogeneous topography, various dynamicand thermal processes take place at mesoscale level. In synoptic scale, during winter seasons, weathersystems, named, western disturbance (WD), take their southerly track and travel over J&K, HP andhills of western UP, and yield considerable amount of precipitation. On the basis of past historicaldata collected over J&K region, the pattern of snowfall and its frequency distribution was studiedusing statistical means. Variation of these snowfall spells was also studied to understand spatial andtemporal changes in their distribution. A brief case study of a WD has been carried out to estimatemoisture flux inflow over Himalayas