Pharmacogenomic Profiling and Pathway Analyses Identify MAPK-Dependent Migration as an Acute Response to SN38 in p53 Null and p53-Mutant Colorectal Cancer Cells.

The topoisomerase I inhibitor irinotecan is used to treat advanced colorectal cancer and has been shown to have p53-independent anticancer activity. The aim of this study was to identify the p53-independent signaling mechanisms activated by irinotecan. Transcriptional profiling of isogenic HCT116 p53 wild-type and p53 null cells was carried out following treatment with the active metabolite of irinotecan, SN38. Unsupervised analysis methods showed that p53 status had a highly significant impact on gene expression changes in response to SN38. Pathway analysis indicated that pathways involved in cell motility [adherens junction, focal adhesion, mitogen-activated protein kinase (MAPK), and regulation of the actin cytoskeleton] were significantly activated in p53 null cells, but not p53 wild-type cells, following SN38 treatment. In functional assays, SN38 treatment increased the migratory potential of p53 null and p53-mutant colorectal cancer cell lines, but not p53 wild-type lines. Moreover, p53 null SN38-resistant cells were found to migrate at a faster rate than parental drug-sensitive p53 null cells, whereas p53 wild-type SN38-resistant cells failed to migrate. Notably, cotreatment with inhibitors of the MAPK pathway inhibited the increased migration observed following SN38 treatment in p53 null and p53-mutant cells. Thus, in the absence of wild-type p53, SN38 promotes migration of colorectal cancer cells, and inhibiting MAPK blocks this potentially prometastatic adaptive response to this anticancer drug.

How intergroup friendship works: A longitudinal study of friendship effects on outgroup attitudes

Cross-sectional research has shown that frequency of self-disclosure to outgroup members mediates the positive relationship between intergroup friendship and outgroup attitudes. The current research investigated the relationship between self-disclosure and attitudes in more depth. New undergraduate students were asked to nominate an ingroup or outgroup friend and then report the intimacy of their disclosures to them, their anxiety and attitudes towards a series of social groups, in the first week of the semester and 6 weeks later. Intimacy of disclosure predicted more positive attitudes towards outgroups over time, but this association was only found among participants who nominated an outgroup friend. In the ingroup friend condition, a negative association was found. These associations were mediated by general intergroup anxiety. These relationships highlight the importance of integrating theories of interpersonal and intergroup relations when investigating intergroup contact. Copyright (C) 2011 John Wiley & Sons, Ltd.

An exploration of the attitudes and strategic responses of soleproprietor micro-enterprises in adopting information and communication technology

This article analyses longitudinal case-based research exploring the attitudes and strategic responses of micro-enterprise owners in adopting information and communication technology (ICT). In so doing, it contributes to the limited literature on micro-enterprise ICT adoption, with a particular focus on sole proprietors. It provides a basis for widening the theoretical base of the literature pertaining to ICT adoption on two levels. First, a framework is developed which integrates the findings to illustrate the relationships between attitudes towards ICT adoption, endogenous and exogenous influencers of these attitudes and subsequent strategic response in ICT adoption. Second, building upon this framework the article reveals the unique challenges, opportunities and implications of ICT adoption for sole-proprietor micro-enterprises. © The Author(s) 2012

Comorbidities and current smoking status amongst patients starting renal replacement therapy in England, Wales and Northern Ireland from 2003 to 2008: national and centre-specific analyses

Introduction: The prevalence of comorbidities in incident renal replacement therapy (RRT) patients changes with age and varies between ethnic groups. This study describes these associations and the independent effect of comorbidities on outcomes. Methods: Adult patients starting RRT between 2003 and 2008 in centres reporting to the UK Renal Registry (UKRR) with data on comorbidity (n ¼ 14,909) were included. The UKRR studied the association of comorbidity with patient demographics, treatment modality, haemoglobin, renal function at start of RRT and subsequent listing for kidney transplantation. The relationship between comorbidities and mortality at 90 days and one year after 90 days from start of RRT was explored using Cox regression. Results: Completeness of comorbidity data was 40.0% compared with 54.3% in 2003. Of patients with data, 53.8% had one or more comorbidities. Diabetes mellitus and ischaemic heart disease were the most common conditions seen in 30.1% and 22.7% of patients respectively. Current smoking was recorded for 14.5% of incident RRT patients in the 6-year period. Comorbidities became more common with increasing age in all ethnic groups although the difference between the 65–74 and 75+ age groups was not significant. Within each age group, South Asians and Blacks had lower rates of comorbidity, despite higher rates of diabetes mellitus. In multivariate survival analysis, malignancy and ischaemic/neuropathic ulcers were the strongest independent predictors of poor survival at 1 year after 90 days from the start of RRT. Conclusion: Differences in prevalence of comorbid illnesses in incident RRT patients may reflect variation in access to health care or competing risk prior to commencing treatment. At the same time, smoking rates remained high in this ‘at risk’ population. Further work on this and ways to improve comorbidity reporting should be priorities for 2010–11.

Comorbidities and current smoking status amongst patients starting renal replacement therapy in England, Wales and Northern Ireland: national and centre-specific analyses

Introduction: The prevalence of 13 comorbid conditions and smoking status at the time of starting renal replacement therapy (RRT) in England, Wales and Northern Ireland are described. Methods: Adult patients starting RRT between 2002 and 2007 in centres reporting to the UK Renal Registry (UKRR) and with data on comorbidity (n¼13,293) were included. The association of comorbidity with patient demographics, treatment modality, haemoglobin, renal function at start of RRT and subsequent listing for kidney transplantation were studied. Association between comorbidities and mortality at 90 days and one year after 90 days from start of RRT was explored using Cox regression. Results: Completeness of data on comorbidity returned to the UKRR remained poor. Of patients with data, 52% had one or more comorbidities. Diabetes mellitus and ischaemic heart disease were the most common conditions seen in 28.9% and 22.5% of patients respectively. Comorbidities became more common with increasing age (up to the 65–74 age group), were more common amongst Whites and were associated with a lower likelihood of pre-emptive transplantation, a greater likelihood of starting on haemodialysis (rather than peritoneal dialysis) and a lower likelihood of being listed for kidney transplantation. In multivariable survival analysis, malignancy and ischaemic/neuropathic ulcers were the strongest predictors of poor survival at 1 year after 90 days from start of RRT. Conclusions: The majority of patients had at least one comorbid condition and comorbidity is an important predictor of early mortality on RRT.

NO3- transport across the plasma membrane of Arabidopsis thaliana root hairs:Kinetic control by pH and membrane voltage

High-affinity nitrate transport was examined in intact root hair cells of Arabidopsis thaliana using electrophysiological recordings to characterise the response of the plasma membrane to NO₃^-challenge and to quantify transport activity. The NO₃^--associated membrane current was determined using a three-electrode voltage clamp to bring membrane voltage under experimental control and to compensate for current dissipation along the longitudinal cell axis. Nitrate transport was evident in the roots of seedlings grown in the absence of a nitrogen source, but only 4-6 days postgermination. In 6-day-old seedlings, additions of 5-100 μm NO₃^-to the bathing medium resulted in membrane depolarizations of 8-43 mV, and membrane voltage (V_m) recovered on washing NO₃^-from the bath. Voltage clamp measurements carried out immediately before and following NO₃^-additions showed that the NO₃^--evoked depolarizations were the consequence of an inward-directed current that appeared across the entire range of accessible voltages (-300 to +50 mV). Both membrane depolarizations and NO₃^--evoked currents recorded at the free-running voltage displayed quasi-Michaelian kinetics, with apparent values for K_m of 23 ± 6 and 44 ± 11 μm, respectively and, for the current, a maximum of 5.1 ± 0.9 μA cm^-2. The NO₃^-current showed a pronounced voltage sensitivity within the normal physiological range between -250 and -100 mV, as could be demonstrated under voltage clamp, and increasing the bathing pH from 6.1 to 7.4-8.0 reduced the current and the associated membrane depolarizations 3- to 8-fold. Analyses showed a well-defined interaction between the kinetic variables of membrane voltage, pH_o and [NO₃^-]_o. At a constant pH_o of 6.1, depolarization from -250 to -150 mV resulted in an approximate 3-fold reduction in the maximum current but a 10% rise in the apparent affinity for NO₃^-. By contrast, the same depolarization effected an approximate 20% fall in the K_m for transport as a function in [H⁺]_o. These, and additional characteristics of the transport current implicate a carrier cycle in which NO₃^-binding is kinetically isolated from the rate-limiting step of membrane charge transit, and they indicate a charge-coupling stoichiometry of 2(H⁺) per NO₃^-anion transported across the membrane. The results concur with previous studies showing a high-affinity NO₃^-transport system in Arabidopsis that is inducible following a period of nitrogen-limiting growth, but they underline the importance of voltage as a kinetic factor controlling NO₃^-transport at the plant plasma membrane. © 1995 Springer-Verlag New York Inc.

Cognitive functioning in subjects with recent-onset psychosis from a low-middle-income environment: Multiple-domain deficits and longitudinal evaluation

Cognitive deficits are a key feature of recent-onset psychosis, but there is no consensus on whether such deficits are generalized or confined to specific domains. Besides, it is unclear whether cognitive deficits: a) are found in psychotic patients in samples from outside high-income countries; and b) whether they progress uniformly over time in schizophrenia and affective psychoses. We applied 12 tests organized into eight cognitive domains, comparing psychosis patients (n = 56, time from initial contact = 677.95+/-183.27 days) versus healthy controls (n = 70) recruited from the same area of Sao Paulo, Brazil. Longitudinal comparisons (digit span and verbal fluency) were conducted between a previous assessment of the subjects carried out at their psychosis onset, and the current follow-up evaluation. Psychosis patients differed significantly from controls on five domains, most prominently on verbal memory. Cognitive deficits remained detectable in separate comparisons of the schizophrenia subgroup and, to a lesser extent, the affective psychosis subjects against controls. Longitudinal comparisons indicated significant improvement in schizophrenia, affective psychoses, and control subjects, with no significant group-by-time interactions. Our results reinforce the view that there are generalized cognitive deficits in association with recent-onset psychoses, particularly of non-affective nature, which persist over time. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Analyzing longitudinal continuity and change in public sector organizations

This article provides the introduction to a special edition that presents for the first time a series of detailed country case studies concerned with the matter of organizational life cycles. Building on some recent scholarship, it begins by surveying the development of the field, before setting out some of the key methodological and theoretical issues and challenges involved in adopting a longitudinal perspective to the study of organizational change. It proposes that by capturing the variety of ways in which public sector organizations emerge, survive, and terminate, new perspectives on how administrative systems evolve can be presented and compared. © Taylor & Francis Group, LLC.

A longitudinal analysis of estimation, counting skills, and mathematical ability across the first school year

In response to claims that the quality (and in particular linearity) of children's mental representation of number acts as a constraint on number development, we carried out a longitudinal assessment of the relationships between number line estimation, counting, and mathematical abilities. Ninety-nine 5-year-olds were tested on 4 occasions at 3 monthly intervals. Correlations between the 3 types of ability were evident, but while the quality of children's estimations changed over time and performance on the mathematical tasks improved over the same period, changes in one were not associated with changes in the other. In contrast to the earlier claims that the linearity of number representation is potentially a unique contributor to children's mathematical development, the data suggest that this variable is not significantly privileged in its impact over and above simple procedural number skills. We propose that both early arithmetic success and estimating skill are bound closely to developments in counting ability.

Exploratory Space-Time Analyses of Rift Valley Fever in South Africa in 2008-2011

Background: Rift Valley fever (RVF) is a zoonotic arbovirosis for which the primary hosts are domestic livestock (cattle, sheep and goats). RVF was first described in South Africa in 1950-1951. Mechanisms for short and long distance transmission have been hypothesised, but there is little supporting evidence. Here we describe RVF occurrence and spatial distribution in South Africa in 2008-11, and investigate the presence of a contagious process in order to generate hypotheses on the different mechanisms of transmission. Methodology/Principal Findings: A total of 658 cases were extracted from World Animal Health Information Database. Descriptive statistics, epidemic curves and maps were produced. The space-time K-function was used to test for evidence of space-time interaction. Five RVF outbreak waves (one in 2008, two in 2009, one in 2010 and one in 2011) of varying duration, location and size were reported. About 70% of cases (n = 471) occurred in 2010, when the epidemic was almost country-wide. No strong evidence of space-time interaction was found for 2008 or the second wave in 2009. In the first wave of 2009, a significant space-time interaction was detected for up to one month and over 40 km. In 2010 and 2011 a significant intense, short and localised space-time interaction (up to 3 days and 15 km) was detected, followed by one of lower intensity (up to 2 weeks and 35 to 90 km). Conclusions/Significance: The description of the spatiotemporal patterns of RVF in South Africa between 2008 and 2011 supports the hypothesis that during an epidemic, disease spread may be supported by factors other than active vector dispersal. Limitations of under-reporting and space-time K-function properties are discussed. Further spatial analyses and data are required to explain factors and mechanisms driving RVF spread. © 2012 Métras et al.

Resolving candidate genes of mouse skeletal muscle QTL via RNA-Seq and expression network analyses

BACKGROUND:

We have recently identified a number of Quantitative Trait Loci (QTL) contributing to the 2-fold muscle weight difference between the LG/J and SM/J mouse strains and refined their confidence intervals. To facilitate nomination of the candidate genes responsible for these differences we examined the transcriptome of the tibialis anterior (TA) muscle of each strain by RNA-Seq.

13,726 genes were expressed in mouse skeletal muscle. Intersection of a set of 1061 differentially expressed transcripts with a mouse muscle Bayesian Network identified a coherent set of differentially expressed genes that we term the LG/J and SM/J Regulatory Network (LSRN). The integration of the QTL, transcriptome and the network analyses identified eight key drivers of the LSRN (Kdr, Plbd1, Mgp, Fah, Prss23, 2310014F06Rik, Grtp1, Stk10) residing within five QTL regions, which were either polymorphic or differentially expressed between the two strains and are strong candidates for quantitative trait genes (QTGs) underlying muscle mass. The insight gained from network analysis including the ability to make testable predictions is illustrated by annotating the LSRN with knowledge-based signatures and showing that the SM/J state of the network corresponds to a more oxidative state. We validated this prediction by NADH tetrazolium reductase staining in the TA muscle revealing higher oxidative potential of the SM/J compared to the LG/J strain (p<0.03).

Thus, integration of fine resolution QTL mapping, RNA-Seq transcriptome information and mouse muscle Bayesian Network analysis provides a novel and unbiased strategy for nomination of muscle QTGs.

Postweaning exposure to aflatoxin results in impaired child growth: A longitudinal study in Benin, west Africa

Aflatoxins are dietary contaminants that are hepatocarcinogenic and immunotoxic and cause growth retardation in animals, but there is little evidence concerning the latter two parameters in exposed human populations. Aflatoxin exposure of West African children is known to be high, so we conducted a longitudinal study over an 8-month period in Benin to assess the effects of exposure on growth. Two hundred children 16-37 months of age were recruited from four villages, two with high and two with low aflatoxin exposure (50 children per village). Serum aflatoxin-albumin (AF-alb) adducts, anthropometric parameters, information on food consumption, and various demographic data were measured at recruitment (February) and at two subsequent time points (June and October). Plasma levels of vitamin A and zinc were also measured. AF-alb adducts increased markedly between February and October in three of the four villages, with the largest increases in the villages with higher exposures. Children who were fully weaned at recruitment had higher AF-alb than did those still partially breast-fed (p < 0.0001); the major weaning food was a maize-based porridge. There was no association between AF-alb and micronutrient levels, suggesting that aflatoxin exposure was not accompanied by a general nutritional deficiency. There was, however, a strong negative correlation (p < 0.0001) between AF-alb and height increase over the 8-month follow-up after adjustment for age, sex, height at recruitment, socioeconomic status, village, and weaning status; the highest quartile of AF-alb was associated with a mean 1.7 cm reduction in growth over 8 months compared with the lowest quartile. This study emphasizes the association between aflatoxin and stunting, although the underlying mechanisms remain unclear. Aflatoxin exposure during the weaning period may be critical in terms of adverse health effects in West African children, and intervention measures to reduce exposure merit investigation.