5-Fluorouracil signaling through a calcium-calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca 2+) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca 2+ through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca 2+ -chelator BAPTA (1,2-bis(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FU-induced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53 -/- cells confirmed the importance of a Ca 2+ -CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes. © 2013 Macmillan Publishers Limited.Swedish Science Foundation; Swedish and Stockholm Cancer Societies; Swedish Childhood Cancer Foundation; EC-FP-6 (Chemores); EC-FP-7 (APO-SYS

Maximum likelihood estimation of locus-specific mutation rates in Y-chromosome short tandem repeats

Motivation: Y-chromosome short tandem repeats (Y-STRs) are widely used for population studies, forensic purposes and, potentially, the study of disease, therefore knowledge of their mutation rate is valuable. Here we show a novel method for estimation of site-specific Y-STR mutation rates from partial phylogenetic information, via the maximum likelihood framework

Communicative Social Justice Training for Resident Advisors: RA’s Experiences and Uses of Training

Resident advisors seek to foster an environment where residents feel safe and included in their residence hall community. Training has become increasingly crucial as the resident advisor role becomes more complex and ambiguous. Not all training is effective and it is important to help resident advisors move from “knowing” what to do to successfully enacting their knowledge in daily interactions. This study examined how resident advisors enact training on social justice topics in conversations with residents on inappropriate behavior, particularly inappropriate behavior that could make others, such as under-represented students, feel offended or excluded. Twelve interviews with both new and mentor resident advisors at a large southwestern university were conducted in order to better understand how resident advisors make sense of their role, experience training, and how they use their training in difficult interactions with residents. Three main themes were identified in analysis: sense making about the RA position is influenced by a relational understanding of the role; training is necessary for the role but also very hard to put into practice; and resident advisors feel that enacting the training is much harder than expected. One particularly interesting finding was that RAs say conversations on inappropriate behavior rarely occur because their floor or residents are unique, positioning their experience as different than others. These findings highlight the challenge for resident advisors to enact their training in conversations when attempting to maintain relationships with their residents

RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide

p120 RasGTPase-activating protein (RasGAP), the main regulator of Ras GTPase family members, is cleaved at low caspase activity into an N-terminal fragment that triggers potent anti-apoptotic signals via activation of the Ras/PI-3 kinase/Akt pathway. When caspase activity is increased, RasGAP fragment N is further processed into two fragments that effectively potentiate apoptosis. Expression of RasGAP protein and its cleavage was assessed in human lung cancer cells with different histology and responsiveness to anticancer drug-induced apoptosis. Here we show that therapy-sensitive small lung carcinoma cell (SCLC) lines have lower RasGAP expression levels and higher spontaneous cleavage with formation of fragment N compared to therapy-resistant non-small cell lung carcinoma cell (NSCLC) lines. The first RasGAP cleavage event strongly correlated with the increased level of spontaneous apoptosis in SCLC. However, generation of protective RasGAP fragment N also related to the potency of SCLC to develop secondary therapy-resistance. In response to etoposide (ET), RasGAP fragment N was further cleaved in direct dependence on caspase-3 activity, which was more pronounced in NSCLC cells. Caspase inhibition, while effectively preventing the second cleavage of RasGAP, barely affected the first cleavage of RasGAP into fragment N that was always detectable in NSCLC and SCLC cells. These findings suggest that different levels of RasGAP and fragment N might play a significant role in the biology and different clinical course of both subtypes of lung neoplasms. Furthermore, constitutive formation of RasGAP fragment N can potentially contribute to primary resistance of NSCLC to anticancer therapy by ET but also to secondary therapy-resistance in SCL

Scientific impact evaluation and the effect of self-citations: mitigating the bias by discounting h-index

In this paper, we propose a measure to assess scientific impact that discounts self-citations and does not require any prior knowledge on the their distribution among publications. This index can be applied to both researchers and journals. In particular, we show that it fills the gap of h-index and similar measures that do not take into account the effect of self-citations for authors or journals impact evaluation. The paper provides with two real-world examples: in the former, we evaluate the research impact of the most productive scholars in Computer Science (according to DBLP); in the latter, we revisit the impact of the journals ranked in the 'Computer Science Applications' section of SCImago. We observe how self-citations, in many cases, affect the rankings obtained according to different measures (including h-index and ch-index), and show how the proposed measure mitigates this effect

Decreased Rate of Evolution in Y Chromosome STR Loci of Increased Size of the Repeat Unit

Polymorphic Y chromosome short tandem repeats (STRs) have been widely used in population genetic and evolutionary studies. Compared to di-, tri-, and tetranucleotide repeats, STRs with longer repeat units occur more rarely and are far less commonly used.In order to study the evolutionary dynamics of STRs according to repeat unit size, we analysed variation at 24 Y chromosome repeat loci: 1 tri-, 14 tetra-, 7 penta-, and 2 hexanucleotide loci. According to our results, penta- and hexanucleotide repeats have approximately two times lower repeat variance and diversity than tri- and tetranucleotide repeats, indicating that their mutation rate is about half of that of tri- and tetranucleotide repeats. Thus, STR markers with longer repeat units are more robust in distinguishing Y chromosome haplogroups and, in some cases, phylogenetic splits within established haplogroups.Our findings suggest that Y chromosome STRs of increased repeat unit size have a lower rate of evolution, which has significant relevance in population genetic and evolutionary studies

Особенности циркуляционных течений в гидротехнических сооружениях

At the article features of circulating currents and their use in vortex spillways are considered at design of high-pressure water-engineering systems. Results of special laboratory researches at which carrying out the certain forms of movement replacing each other in certain sequence are recorded are given. At the experiences with the twirled stream similar structures, and also area existence with a contraflow in the central part and its influence on integrated characteristics of a circulating stream in a pipe are found.В статье рассматриваются особенности циркуляционных течений и их использование в вихревых водосбросах при проектировании высоконапорных гидроузлов. Приводятся результаты специальных лабораторных исследований, при проведении которых зафиксированы определенные формы движения, сменяющие друг друга в определенной последовательности. В опытах с закрученной струей обнаружены аналогичные структуры, а также наличие области с обратным течением в центральной части и ее влияние на интегральные характеристики циркуляционного потока в трубе

Non-linear regression models for Approximate Bayesian Computation

Approximate Bayesian inference on the basis of summary statistics is well-suited to complex problems for which the likelihood is either mathematically or computationally intractable. However the methods that use rejection suffer from the curse of dimensionality when the number of summary statistics is increased. Here we propose a machine-learning approach to the estimation of the posterior density by introducing two innovations. The new method fits a nonlinear conditional heteroscedastic regression of the parameter on the summary statistics, and then adaptively improves estimation using importance sampling. The new algorithm is compared to the state-of-the-art approximate Bayesian methods, and achieves considerable reduction of the computational burden in two examples of inference in statistical genetics and in a queueing model.Comment: 4 figures; version 3 minor changes; to appear in Statistics and Computin

New findings to discussion on local versus fluctuating stocks of pink salmon <i>Oncorhynchus gorbuscha</i>

Some patterns in dynamics of catch and biological parameters of pink salmon Oncorhynchus gorbuscha returned to the southeastern coast of Sakhalin Island and the Aniva Bay in 2014 (additional peak in the return abundance and unusual increase in relative fecundity of females in the second half of the return) could be interpreted as presence of the fish from Kuril Islands. This hypothesis was proven by the scale structure analysis, using the known difference between the pink salmon from southern Sakhalin and Iturup Island by the total number of sclerites and the depth of the local minimum in the first eight intersclerite distances caused by different environments. The fish of Kuril origin was found in all samples collected on the southeastern coast of Sakhalin on August 6, 7, 14, and 18, with its portion increasing in later catches, and in the sample collected in the Ostrovka River on the eastern shore of the Aniva Bay on August 18, but wasn’t found in the sample collected in the same site on August 25, and only a small portion of the fish of Kuril origin was found in the marine sample taken at the Busse Lagoon. The pink salmon in the Kura River on the western shore of the Aniva Bay had mixed origin, too, but without signs of the Kuril origin. This is the first real evidence of the salmon straying and the hypothesis of fluctuating stocks of pink salmon obtained with the ichthyological methods, though possibility of the straying is debating many years. This phenomenon has high theoretical and practical importance. The new findings show that mass movement of pink salmon between different reproduction regions is quite real, though maybe it happens rarely, presumably during the shift of domination between the odd- and even-year broodlines. The straying of low intensity may be invisible with routine methods, that’s why thorough monitoring of pink salmon stocks in different areas of its reproduction is necessary for understanding its population structure and dynamics, including detailed environmental, ichthyological and genetic studies