Predicting rare events in chemical reactions: application to skin cell proliferation

In a well-stirred system undergoing chemical reactions, fluctuations in the reaction propensities are approximately captured by the corresponding chemical Langevin equation. Within this context, we discuss in this work how the Kramers escape theory can be used to predict rare events in chemical reactions. As an example, we apply our approach to a recently proposed model on cell proliferation with relevance to skin cancer [P.B. Warren, Phys. Rev. E {\bf 80}, 030903 (2009)]. In particular, we provide an analytical explanation for the form of the exponential exponent observed in the onset rate of uncontrolled cell proliferation.Comment: New materials and references added. To appear in Physical Review

Transfer Pricing of Intangible Assets in the US, the OECD and Australia: Are Profit-Split Methodologies the Way Forward?

In the 21st century, the number one international tax issue of interest to multinational enterprises (MNEs) is undoubtedly transfer pricing. The reason for this is that as global trade increases, so too does the uncertainty of the tax treatment of inter-affiliate transactions across national boundaries and the spectre of double taxation. The Australian Deputy Commissioner of Taxation has outlined the concept of transfer pricing as follows: 'Broadly, transfer pricing relates to the setting of prices by multinationals for the goods and services that they supply to related parties. It also covers the structuring of transactions and financial relationships, and how innovation happens and is rewarded.' The OECD Transfer Pricing Guidelines for Multinational Enterprises and Tax Administrations (the OECD Guidelines) make it clear that the concept of transfer pricing should not be confused with that of tax fraud, or of tax avoidance, even though transfer pricing transactions may be utilised for such purposes. A number of international tax specialists have also stressed that incorrect references to transfer pricing as 'income-shifting' obfuscate a clear analysis. A paper prepared by the United Nations Secretariat in 2001 has described transfer pricing as 'probably the most important tax issue in the world'. Referring to the fact that over 60 percent of international trade is carried out within MNEs, the paper also refers to the impact which intangible property has had on this trade. Both US and Australian tax practitioners have acknowledged that some of the most difficult transfer pricing issues have always been in the area of intangible property. The tax treatment of intangible assets therefore warrants particular attention in the transfer pricing context. In the United States, for purposes of section 482 of the final regulations, the term 'intangible' refers to any item included in one of six broad categories specified in the regulations, provided the item has substantial value independent of the services of any individual. These categories of intangible property include: • Patents, inventions, formulas, processes, designs, patterns or know-how; • Copyrights and literary, musical, or artistic compositions; • Trademarks, trade names, or brand names; • Franchises, licenses, or contracts; • Methods, programs, systems, procedures, campaigns, surveys, studies, forecasts, estimates, customer lists, or technical data; and • Any other similar item that derives its value from its intellectual content rather than its physical attributes. For the purposes of Chapter VI of the OECD Guidelines, 'intangible property' includes rights to use industrial assets, such as patents, trademarks, trade names, designs or models, literary and artistic property rights, and intellectual property such as know-how and trade secrets. Australian Taxation Rulings generally refer to the OECD definitions of intangible assets. The internationally accepted arm's length principle demands that MNEs charge transfer prices in their controlled transactions that are consistent with the prices that would have been charged for the same uncontrolled transaction taking place between unrelated, independent enterprises under the same circumstances. To this end, transfer pricing methodologies are utilised by MNEs in order to establish an arm's length outcome. The transfer pricing methodology adopted by an MNE consequently constitutes a pivotal component of a determination of the arm's length consideration attributable to a transaction involving the intragroup transfer of intangible property. As identical transactions between unrelated enterprises are rare, transfer pricing methodologies tend to focus on comparable rather than identical transactions. So-called 'transactional' methodologies have been espoused by revenue authorities as the most direct way of establishing whether arm's length conditions exist between associated enterprises. These methodologies are reliant on finding either identical transactions, or, where these are not available, similar comparable transactions. There has been a growing realisation that where intangible assets are concerned, there are grave problems in determining even a comparative analysis. This paper will explore the consequent shifting focus to newer, non-traditional methodologies, especially profit-split methodologies, in the US and Australia, and to a lesser extent by the OECD. These methodologies tend to rely in whole or in part on internal data rather than on data derived from comparable uncontrolled transactions. The US final section 482 regulations , the OECD Guidelines and the Australian transfer pricing rulings all permit MNEs to select an appropriate transfer pricing methodology for their inter-affiliate transfers of intangible assets. Different methodologies may be selected under different circumstances. It is necessary to assess a number of variables in determining the correct methodology for a particular transaction. These variables may change over time, necessitating a reconsideration of the methodology to be utilised. Although there are marked similarities in the US, OECD and Australian approaches to choosing a transfer pricing methodology for intangible property transfers, there are also some important differences. While the official position of the US is that its final transfer pricing regulations are consistent with the OECD Guidelines, some OECD member countries disagree. This has had the unfortunate result that MNEs risk antagonising certain revenue authorities if they undertake what appears to be a US transfer pricing approach. Multinational taxpayers are therefore compelled 'to account for multiple and sometime[s] disparate rules when setting, documenting, and defending cross-border transfer prices.

Fluctuations and noise in cancer development

This paper explores fluctuations and noise in various facets of cancer development. The three areas of particular focus are the stochastic progression of cells to cancer, fluctuations of the tumor size during treatment, and noise in cancer cell signalling. We explore the stochastic dynamics of tumor growth and response to treatment using a Markov model, and fluctutions in tumor size in response to treatment using partial differential equations. We also explore noise within gene networks in cancer cells, and noise in inter-cell signalling.Comment: 11 pages, 6 figure

Pink1 and Parkin regulate Drosophila intestinal stem cell proliferation during stress and aging.

Intestinal stem cells (ISCs) maintain the midgut epithelium in Drosophila melanogaster Proper cellular turnover and tissue function rely on tightly regulated rates of ISC division and appropriate differentiation of daughter cells. However, aging and epithelial injury cause elevated ISC proliferation and decreased capacity for terminal differentiation of daughter enteroblasts (EBs). The mechanisms causing functional decline of stem cells with age remain elusive; however, recent findings suggest that stem cell metabolism plays an important role in the regulation of stem cell activity. Here, we investigate how alterations in mitochondrial homeostasis modulate stem cell behavior in vivo via RNA interference-mediated knockdown of factors involved in mitochondrial dynamics. ISC/EB-specific knockdown of the mitophagy-related genes Pink1 or Parkin suppresses the age-related loss of tissue homeostasis, despite dramatic changes in mitochondrial ultrastructure and mitochondrial damage in ISCs/EBs. Maintenance of tissue homeostasis upon reduction of Pink1 or Parkin appears to result from reduction of age- and stress-induced ISC proliferation, in part, through induction of ISC senescence. Our results indicate an uncoupling of cellular, tissue, and organismal aging through inhibition of ISC proliferation and provide insight into strategies used by stem cells to maintain tissue homeostasis despite severe damage to organelles

On the dynamics of social conflicts: looking for the Black Swan

This paper deals with the modeling of social competition, possibly resulting in the onset of extreme conflicts. More precisely, we discuss models describing the interplay between individual competition for wealth distribution that, when coupled with political stances coming from support or opposition to a government, may give rise to strongly self-enhanced effects. The latter may be thought of as the early stages of massive, unpredictable events known as Black Swans, although no analysis of any fully-developed Black Swan is provided here. Our approach makes use of the framework of the kinetic theory for active particles, where nonlinear interactions among subjects are modeled according to game-theoretical tools.Comment: 26 pages, 7 figure

Advances in Chimeric Antigen Receptor T-Cell Therapies for Solid Tumors.

In 2017, the US Food and Drug Administration approved the first two novel cellular immunotherapies using synthetic, engineered receptors known as chimeric antigen receptors (CARs), tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient-derived T cells for the treatment of hematological malignancies expressing the B-cell surface antigen CD19 in both pediatric and adult patients. This approval marked a major milestone in the use of antigen-directed living drugs for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be targeted. This state-of-the-art review will focus on the challenges, advances, and novel approaches being used to implement CAR T-cell immunotherapy for the treatment of solid tumors

The characteristics of retail wastes in the city of Yenagoa, Nigeria

&lt;p class="EbiBody"&gt;&lt;strong&gt;Wastes management is a clear strategy where wastes are channelled through processes that ensures proper storage, collection, transportation, treatment and disposal of wastes with ample consideration for environmental protection and public health. In Yenagoa where the current study was conducted, the lack of proper wastes management structure is apparent, particularly among retailers where samples were drawn from for the study. Little is known on the volume and characteristics of wastes produced by the retail sector in the city, like many other Nigerian cities.&lt;/strong&gt;&lt;/p&gt;&lt;p class="EbiBody"&gt;The study employed a mixed method approach using closed and open-ended questionnaires in collecting data. In all about 900 questionnaires were collected and analysed for the study. Knowing that no proper waste management plan can be developed until the current practice, sources, components and volume of waste has been well understood. The use of qualitative methods in this paper helps to better understand and gather data on areas of interest. A multi stage cluster sampling technique was employed due to the unavailability of an up-to-date sampling frame in the area.&lt;/p&gt;&lt;p class="EbiBody"&gt;The findings from the study show that wastes materials produced by retailers in Yenagoa are mainly wastes paper, tins, cans, plastics, cardboard, furniture, wood products and possibly WEEE. However, plastics and cardboard materials were the dominant wastes materials produced by the retail sector. The study therefore concludes that there is a need to establish a wastes processing facility in Yenagoa with heavy emphasis on recycling.&lt;/p&gt;</jats:p