Predicting the safety and efficacy of butter therapy to raise tumour pHe: an integrative modelling study

Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts.\ud \ud Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies.\ud \ud Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2.\ud \ud Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising

Mexico City and the biogeochemistry of global urbanization

Mexico City is far advanced in its urban evolution, and cities in currently developing nations may soon follow a similar course. This paper investigates the strengths and weaknesses of infrastructures for the emerging megacities. The major driving force for infrastructure change in Mexico City is concern over air quality. Air chemistry data from recent field campaigns have been used to calculate fluxes in the atmosphere of the Valley of Mexico, for compounds that are important to biogeochemistry including methane (CH4), carbon monoxide (CO), nonmethane hydrocarbons (NMHCs), ammonia (NH3), sulfur dioxide (SO2), nitrogen oxides (NOx and NOy), soot, and dust. Leakage of liquified petroleum gas approached 10% during sampling periods, and automotive pollutant sources in Mexico City were found to match those in developed cities, despite a lower vehicle-to-person ratio of 0.1. Ammonia is released primarily from residential areas, at levels sufficient to titrate pollutant acids into particles across the entire basin. Enhancements of reduced nitrogen and hydrocarbons in the vapor phase skew the distribution of NOy species towards lower average deposition velocities. Partly as a result, downwind nutrient deposition occurs on a similar scale as nitrogen fixation across Central America, and augments marine nitrate upwelling. Dust suspension from unpaved roads and from the bed of Lake Texcoco was found to be comparable to that occurring on the periphery of the Sahara, Arabian, and Gobi deserts. In addition, sodium chloride (NaCl) in the dust may support heterogeneous chlorine oxide (ClOx) chemistry. The insights from our Mexico City analysis have been tentatively applied to the upcoming urbanization of Asia

Principles of Stakes Fairness in Sport

Fairness in sport is not just about assigning the top prizes to the worthiest competitors. It is also about the way the prize structure itself is organised. For many sporting competitions, although it may be acceptable for winners to receive more than losers, it can seem unfair for winners to take everything and for losers to get nothing. Yet this insight leaves unanswered some difficult questions about what stakes fairness requires and which principles of stakes fairness are appropriate for particular competitions. In this article I specify a range of different principles of stakes fairness (ten in total) that could regulate sporting competitions. I also put forward a theoretical method for pairing up appropriate principles of stakes fairness with given sporting competitions. Specifically, I argue that the underlying rationales for holding sporting competitions can provide useful guides for identifying appropriate principles of stakes fairness. I then seek to clarify and work through some of the implications of this method for a sample of real world controversies over sporting prize structures. I also attempt to refine the method in response to two possible objections from indeterminacy and relativism. Finally, I compare and contrast my conclusions with more general philosophical debates about justice

A general reaction-diffusion model of acidity in cancer invasion

We model the metabolism and behaviour of a developing cancer tumour in the context of its microenvironment, with the aim of elucidating the consequences of altered energy metabolism. Of particular interest is the Warburg Effect, a widespread preference in tumours for cytosolic glycolysis rather than oxidative phosphorylation for glucose breakdown, as yet incompletely understood. We examine a candidate explanation for the prevalence of the Warburg Effect in tumours, the acid-mediated invasion hypothesis, by generalising a canonical non-linear reaction–diffusion model of acid-mediated tumour invasion to consider additional biological features of potential importance. We apply both numerical methods and a non-standard asymptotic analysis in a travelling wave framework to obtain an explicit understanding of the range of tumour behaviours produced by the model and how fundamental parameters govern the speed and shape of invading tumour waves. Comparison with conclusions drawn under the original system—a special case of our generalised system—allows us to comment on the structural stability and predictive power of the modelling framework

Contextual adaptation of the Personnel Evaluation Standards for assessing faculty evaluation systems in developing countries: the case of Iran

<p>Abstract</p> <p>Background</p> <p>Faculty evaluations can identify needs to be addressed in effective development programs. Generic evaluation models exist, but these require adaptation to a particular context of interest. We report on one approach to such adaptation in the context of medical education in Iran, which is integrated into the delivery and management of healthcare services nationwide.</p> <p>Methods</p> <p>Using a triangulation design, interviews with senior faculty leaders were conducted to identify relevant areas for faculty evaluation. We then adapted the published checklist of the Personnel Evaluation Standards to fit the Iranian medical universities' context by considering faculty members' diverse roles. Then the adapted instrument was administered to faculty at twelve medical schools in Iran.</p> <p>Results</p> <p>The interviews revealed poor linkages between existing forms of development and evaluation, imbalance between the faculty work components and evaluated areas, inappropriate feedback and use of information in decision making. The principles of Personnel Evaluation Standards addressed almost all of these concerns and were used to assess the existing faculty evaluation system and also adapted to evaluate the core faculty roles. The survey response rate was 74%. Responses showed that the four principles in all faculty members' roles were met <it>occasionally </it>to <it>frequently</it>. Evaluation of teaching and research had the highest mean scores, while clinical and healthcare services, institutional administration, and self-development had the lowest mean scores. There were statistically significant differences between small medium and large medical schools (p < 0.000).</p> <p>Conclusion</p> <p>The adapted Personnel Evaluation Standards appears to be valid and applicable for monitoring and continuous improvement of a faculty evaluation system in the context of medical universities in Iran. The approach developed here provides a more balanced assessment of multiple faculty roles, including educational, clinical and healthcare services. In order to address identified deficiencies, the evaluation system should recognize, document, and uniformly reward those activities that are vital to the academic mission. Inclusion of personal developmental concerns in the evaluation discussion is essential for evaluation systems.</p

Purification and preliminary characterization of a xylanase from Thermomyces lanuginosus strain SS-8

Thermomyces lanuginosus SS-8 was isolated from soil samples that had been collected from near self-heating plant material and its extracellular cellulase-free xylanase purified approximately 160-fold using ion exchange chromatography and continuous elution electrophoresis. This xylanase was thermoactive (optimum temperature 60 °C) at pH 6.0 and had a molecular weight of 23.79 kDa as indicated by SDS-PAGE electrophoresis. The xylanase rapidly hydrolyzed xylan directly to xylose without the production of intermediary xylo-oligosaccharides within 15 min of incubation under optimum conditions. This trait of rapidly degrading xylan to xylose as a sole end-product could have biotechnological potential in degradation of agro-wastes for bioethanol manufacturing industry

A Selection Index for Gene Expression Evolution and Its Application to the Divergence between Humans and Chimpanzees

The importance of gene regulation in animal evolution is a matter of long-standing interest, but measuring the impact of selection on gene expression has proven a challenge. Here, we propose a selection index of gene expression as a straightforward method for assessing the mode and strength of selection operating on gene expression levels. The index is based on the widely used McDonald-Kreitman test and requires the estimation of four quantities: the within-species and between-species expression variances as well as the sequence heterozygosity and divergence of neutrally evolving sequences. We apply the method to data from human and chimpanzee lymphoblastoid cell lines and show that gene expression is in general under strong stabilizing selection. We also demonstrate how the same framework can be used to estimate the proportion of adaptive gene expression evolution

Hypermutable Non-Synonymous Sites Are under Stronger Negative Selection

Mutation rate varies greatly between nucleotide sites of the human genome and depends both on the global genomic location and the local sequence context of a site. In particular, CpG context elevates the mutation rate by an order of magnitude. Mutations also vary widely in their effect on the molecular function, phenotype, and fitness. Independence of the probability of occurrence of a new mutation's effect has been a fundamental premise in genetics. However, highly mutable contexts may be preserved by negative selection at important sites but destroyed by mutation at sites under no selection. Thus, there may be a positive correlation between the rate of mutations at a nucleotide site and the magnitude of their effect on fitness. We studied the impact of CpG context on the rate of human–chimpanzee divergence and on intrahuman nucleotide diversity at non-synonymous coding sites. We compared nucleotides that occupy identical positions within codons of identical amino acids and only differ by being within versus outside CpG context. Nucleotides within CpG context are under a stronger negative selection, as revealed by their lower, proportionally to the mutation rate, rate of evolution and nucleotide diversity. In particular, the probability of fixation of a non-synonymous transition at a CpG site is two times lower than at a CpG site. Thus, sites with different mutation rates are not necessarily selectively equivalent. This suggests that the mutation rate may complement sequence conservation as a characteristic predictive of functional importance of nucleotide sites

Toll-like receptors in cellular subsets of human tonsil T cells: altered expression during recurrent tonsillitis

BACKGROUND: The palatine tonsils have a pivotal role in immunological detection of airborne and ingested antigens like bacteria and viruses. They have recently been demonstrated to express Toll-like receptors (TLRs), known to recognize molecular structures on such microbes and activate innate immune responses. Their activation might also provide a link between innate and adaptive immunity. In the present study, the expression profile of TLR1-TLR10 was characterized in human tonsil T cells, focusing on differences between subsets of CD4(+ )T helper (Th) cells and CD8(+ )cytotoxic T lymphocytes (CTL). The study was also designed to compare the TLR expression in T cells from patients with recurrent tonsillitis and tonsillar hyperplasia. METHODS: Tonsils were obtained from children undergoing tonsillectomy, and classified according to the clinical diagnoses and the outcome of tonsillar core culture tests. Two groups were defined; recurrently infected tonsils and hyperplastic tonsils that served as controls. Subsets of T cells were isolated using magnetic beads. The expression of TLR transcripts in purified cells was assessed using quantitative real-time RT-PCR. The corresponding protein expression was investigated using flow cytometry and immunohistochemistry. RESULTS: T cells expressed a broad repertoire of TLRs, in which TLR1, TLR2, TLR5, TLR9 and TLR10 predominated. Also, a differential expression of TLRs in CD4(+ )and CD8(+ )T cells was obtained. TLR1 and TLR9 mRNA was expressed to a greater extent in CD4(+ )cells, whereas expression of TLR3 mRNA and protein and TLR4 protein was higher in CD8(+ )cells. CD8(+ )cells from infected tonsils expressed higher levels of TLR2, TLR3 and TLR5 compared to control. In contrast, CD4(+ )cells exhibited a down-regulated TLR9 as a consequence of infection. CONCLUSION: The present study demonstrates the presence of a broad repertoire of TLRs in T cells, a differential expression in CD4(+ )and CD8(+ )cells, along with infection-dependent alterations in TLR expression. Collectively, these results support the idea that TLRs are of importance to adaptive immune cells. It might be that TLRs have a direct role in adaptive immune reactions against infections. Thus, further functional studies of the relevance of TLR stimulation on T cells will be of importance