CCI52 sensitizes tumors to 6-mercaptopurine and inhibits MYCN-amplified tumor growth

The antimetabolite 6-mercaptopurine (6-MP) is an important component in the treatment of specific cancer subtypes, however, the development of drug resistance and dose-limiting toxicities can limit its effectiveness. The therapeutic activity of 6-MP requires cellular uptake, enzymatic conversion to thio-GMP and incorporation of thio-GTP into RNA and DNA, as well as inhibition of de novo purine synthesis by methyl-thio-IMP. Mechanisms that prevent 6-MP entry into the cell, prevent 6-MP metabolism or deplete thiopurine intermediates, can all lead to 6-MP resistance. We previously conducted a high-throughput screen for inhibitors of the multidrug transporter MRP4 using 6-MP sensitivity as the readout. In addition to MRP4-specific inhibitors, we identified a compound, CCI52, that sensitized cell lines to 6-MP independent of this transporter. CCI52 and its more stable analogue CCI52-14 also function as effective chemosensitizers in vivo, substantially extending survival in a transgenic mouse cancer model treated with 6-MP. Chemosensitization was associated with an increase in thio-IMP, suggesting that CCI52 functions directly on 6-MP uptake or metabolism. In addition to its chemosensitizing effects, CCI52 and CCI52-14 inhibited the growth of MYCN-amplified high-risk neuroblastoma cell lines and delayed tumor progression in a MYCN-driven, transgenic mouse model of neuroblastoma. These multifunctional inhibitors may be useful for the further development of anticancer agents and as tools to better understand 6-MP metabolism

Extragalactic Radio Continuum Surveys and the Transformation of Radio Astronomy

Next-generation radio surveys are about to transform radio astronomy by discovering and studying tens of millions of previously unknown radio sources. These surveys will provide new insights to understand the evolution of galaxies, measuring the evolution of the cosmic star formation rate, and rivalling traditional techniques in the measurement of fundamental cosmological parameters. By observing a new volume of observational parameter space, they are also likely to discover unexpected new phenomena. This review traces the evolution of extragalactic radio continuum surveys from the earliest days of radio astronomy to the present, and identifies the challenges that must be overcome to achieve this transformational change.Comment: To be published in Nature Astronomy 18 Sept 201

Cross-Clade Recognition of HIV-1 CAp24 by CD4+ T Cells in HIV-1-Infected Individuals in Burkina Faso and Germany

The presence of antigen-specific cellular immune responses may be an indicator of long-term asymptomatic HIV-1-disease. The detection of cellular immune responses to infection with different subtypes of HIV-1 may be hampered by genetic differences of immunodominant antigens such as the capsid protein CAp24. In Nouna, Burkina Faso, HIV-1 circulating recombinant forms CRF02_AG and CRF06_cpx are the 2 major strains detectable in HIV-1-infected individuals, while subtype B strains prevail in Europe and North America. Amino acid sequences of CAp24 were assessed in blood samples from 10 HIV-1-infected patients in Nouna, Burkina Faso. Production of interferon-gamma (IFN-γ) in peripheral blood CD4+ lymphocytes in response to recombinant HIV-1 proteins derived from clade B (including CAp24NL4-3) was measured using a modified flow-cytometry-based whole blood short term activation assay (FASTimmune, BDBiosciences). IFN-γ production following stimulation with a whole length CAp24 protein derived from clade B (CAp24NL4-3) was additionally quantified in comparison to a CAp24 protein derived from CRF02_AG (CAp24BD6-15) in 16 HIV-1-infected patients in Heidelberg, Germany. Amino acid sequence identity of CAp24 obtained from patients in Nouna ranged between 86 and 89% when compared to the clade B CAp24NL4-3 consensus sequence, between 90 and 95% when compared to the circulating recombinant form CRF06_CPX consensus sequence, and between 92 and 96% when compared to the CAp24BD6-15 consensus sequence. Significant numbers of HIV-1-specific CD4+ lymphocytes producing IFN-γ were detected in 4 of 10 HIV-1-infected patients. In 7 of 16 patients in Heidelberg, recombinant CAp24BD6-15 stimulated IFN-γ-production in CD4+ lymphocytes to a similar extent as the clade B-derived CAp24NL4-3. Thus, antigen-specific CD4+ lymphocytes from both West African and European patients infected with different strains of HIV-1 show relevant cross-clade recognition of HIV-1 CAp24 in a flow-cytometry-based whole blood short term activation assay

Internal accounting practices at Whitbread & Company c.1890-1925

This paper examines internal accounting practices at Whitbread & Company from c. 1890 to 1925. At this time, there was an increasing interest in cost accounting, but there is little detailed extant research on general internal accounting practices of firms. The brewing sector, we suggest, is a potentially fruitful realm to further our knowledge of this time. Drawing on the Whitbread brewery archival records, we chart the internal accounting practices of the company. Our findings reveal a stable set of accounting practices, focused mainly on bookkeeping, although the firm’s auditor produced some reports which may have been useful for management decision-making. We argue these practices were highly institutionalised, and seemingly resistant to external forces present in the company’s environment

Valence-Specific Modulation in the Accumulation of Perceptual Evidence Prior to Visual Scene Recognition

Visual scene recognition is a dynamic process through which incoming sensory information is iteratively compared with predictions regarding the most likely identity of the input stimulus. In this study, we used a novel progressive unfolding task to characterize the accumulation of perceptual evidence prior to scene recognition, and its potential modulation by the emotional valence of these scenes. Our results show that emotional (pleasant and unpleasant) scenes led to slower accumulation of evidence compared to neutral scenes. In addition, when controlling for the potential contribution of non-emotional factors (i.e., familiarity and complexity of the pictures), our results confirm a reliable shift in the accumulation of evidence for pleasant relative to neutral and unpleasant scenes, suggesting a valence-specific effect. These findings indicate that proactive iterations between sensory processing and top-down predictions during scene recognition are reliably influenced by the rapidly extracted (positive) emotional valence of the visual stimuli. We interpret these findings in accordance with the notion of a genuine positivity offset during emotional scene recognition

Conflict of Interest in Clinical Practice Guideline Development: A Systematic Review

Background: There is an emerging literature on the existence and effect of industry relationships on physician and researcher behavior. Much less is known, however, about the effects of these relationships and other conflicts of interest (COI) on clinical practice guideline (CPG) development and recommendations. We performed a systematic review of the prevalence of COI and its effect on CPG recommendations. Methodology/Principal Findings: We searched Medline (1980 to March, 2011) for studies that examined the effect of COI on CPG development and/or recommendations. Data synthesis was qualitative. Twelve studies fulfilled inclusion criteria; 9 were conducted in the US. All studies reported on financial relationships of CPG authors with the pharmaceutical industry; 1 study also examined relationships with diagnostic testing and insurance companies. The majority of guidelines had authors with industry affiliations, including consultancies (authors with relationship, range 6–80%); research support (4–78%); equity/stock ownership (2–17%); or any COI (56–87%). Four studies reported multiple types of financial interactions for individual authors (number of types per author: range 2 to 10 or more). Data on the effect of COI on CPG recommendations were confined to case studies wherein authors with specific financial ties appeared to benefit from the related CPG recommendations. In a single study, few authors believed that their relationships influenced their recommendations. No studies reported on intellectual COI in CPGs

Quantitative permeability imaging of plant tissues

A method for mapping tissue permeability based on time-dependent diffusion measurements is presented. A pulsed field gradient sequence to measure the diffusion encoding time dependence of the diffusion coefficients based on the detection of stimulated spin echoes to enable long diffusion times is combined with a turbo spin echo sequence for fast NMR imaging (MRI). A fitting function is suggested to describe the time dependence of the apparent diffusion constant in porous (bio-)materials, even if the time range of the apparent diffusion coefficient is limited due to relaxation of the magnetization. The method is demonstrated by characterizing anisotropic cell dimensions and permeability on a subpixel level of different tissues of a carrot (Daucus carota) taproot in the radial and axial directions

MRI of intact plants

Nuclear magnetic resonance imaging (MRI) is a non-destructive and non-invasive technique that can be used to acquire two- or even three-dimensional images of intact plants. The information within the images can be manipulated and used to study the dynamics of plant water relations and water transport in the stem, e.g., as a function of environmental (stress) conditions. Non-spatially resolved portable NMR is becoming available to study leaf water content and distribution of water in different (sub-cellular) compartments. These parameters directly relate to stomatal water conductance, CO2 uptake, and photosynthesis. MRI applied on plants is not a straight forward extension of the methods discussed for (bio)medical MRI. This educational review explains the basic physical principles of plant MRI, with a focus on the spatial resolution, factors that determine the spatial resolution, and its unique information for applications in plant water relations that directly relate to plant photosynthetic activity

Risk factors for the onset and persistence of neck pain in undergraduate students: 1-year prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Although neck pain is common in young adulthood, studies on predictive factors for its onset and persistence are scarce. It is therefore important to identify possible risk factors among young adults so as to prevent the development of neck pain later in life.</p> <p>Methods</p> <p>A prospective study was carried out in healthy undergraduate students. At baseline, a self-administered questionnaire and standardized physical examination were used to collect data on biopsychosocial factors. At 3, 6, 9, and 12 months thereafter, follow-up data were collected on the incidence of neck pain. Those who reported neck pain on ≥ 2 consecutive follow-ups were categorized as having persistent neck pain. Two regression models were built to analyze risk factors for the onset and persistence of neck pain.</p> <p>Results</p> <p>Among the recruited sample of 684 students, 46% reported the onset of neck pain between baseline and 1-year follow-up, of whom 33% reported persistent neck pain. The onset of neck pain was associated with computer screen position not being level with the eyes and mouse position being self-rated as suitable. Factors that predicted persistence of neck pain were position of the keyboard being too high, use of computer for entertainment < 70% of total computer usage time, and students being in the second year of their studies.</p> <p>Conclusion</p> <p>Neck pain is quite common among undergraduate students. This study found very few proposed risk factors that predicted onset and persistence of neck pain. The future health of undergraduate students deserves consideration. However, there is still much uncertainty about factors leading to neck pain and more research is needed on this topic.</p

Impact of Dietary Gluten on Regulatory T Cells and Th17 Cells in BALB/c Mice

Dietary gluten influences the development of type 1 diabetes (T1D) and a gluten-free (GF) diet has a protective effect on the development of T1D. Gluten may influence T1D due to its direct effect on intestinal immunity; however, these mechanisms have not been adequately studied. We studied the effect of a GF diet compared to a gluten-containing standard (STD) diet on selected T cell subsets, associated with regulatory functions as well as proinflammatory Th17 cells, in BALB/c mice. Furthermore, we assessed diet-induced changes in the expression of various T cell markers, and determined if changes were confined to intestinal or non-intestinal lymphoid compartments. The gluten-containing STD diet led to a significantly decreased proportion of γδ T cells in all lymphoid compartments studied, although an increase was detected in some γδ T cell subsets (CD8+, CD103+). Further, it decreased the proportion of CD4+CD62L+ T cells in Peyer's patches. Interestingly, no diet-induced changes were found among CD4+Foxp3+ T cells or CD3+CD49b+cells (NKT cells) and CD3−CD49b+ (NK) cells. Mice fed the STD diet showed increased proportions of CD4+CD45RBhigh+ and CD103+ T cells and a lower proportion of CD4+CD45RBlow+ T cells in both mucosal and non-mucosal compartments. The Th17 cell population, associated with the development of autoimmunity, was substantially increased in pancreatic lymph nodes of mice fed the STD diet. Collectively, our data indicate that dietary gluten influences multiple regulatory T cell subsets as well as Th17 cells in mucosal lymphoid tissue while fewer differences were observed in non-mucosal lymphoid compartments