Whither systems biology

Cell biologists are interested in how complexity arises from the interaction of different molecules. However, cells are many orders of magnitude larger than the protein-binding interfaces. To bridge these vast difference in scales, biologists construct hierarchies of organization of cellular structures. I describe how systems biology provides an approach to bridge these different scales

Challenging the orthodoxy: union learning representatives as organic intellectuals

Teacher education and continuing professional development have become a key areas of controversy in England since the period of school sector restructuring following the 1988 Education Reform Act. More recently teacher training and professional development have often been used to promote and reinforce a narrow focus on the government’s ‘standards agenda’. However, the emerging discourse of ‘new professionalism’ has raised the profile of professional development in schools, and together with union learning representatives, there are opportunities to secure real improvements in teachers’ access to continuing professional development. This paper argues however that union learning representatives must go beyond advocating for better access to professional development and should raise more fundamental questions about the nature of professional development and the education system it serves. Drawing on Gramsci’s notion of the ‘organic intellectual’, the paper argues that union learning representatives have a key role as organisers of ideas – creating spaces in which the ideological dominance of current policy orthodoxy might be challenged

First-in-human, open-label dose-escalation and dose-expansion study of the safety, pharmacokinetics, and antitumor effects of an oral ALK inhibitor ASP3026 in patients with advanced solid tumors

Abstract Background ASP3026 is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has potent in vitro activity against crizotinib-resistant ALK-positive tumors. This open-label, multicenter, first-in-human phase I study ( NCT01284192 ) assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026. Methods Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25–800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK-positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1. Results The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK-positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC) patients. ASP3026 demonstrated both linear pharmacokinetics and dose-proportional exposure for area under the plasma concentration–time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38 %), fatigue (35 %), and vomiting (35 %). Among the 16 patients with crizotinib-resistant ALK-positive tumors (15 NSCLC, 1 neuroblastoma), eight patients achieved partial response (overall response rate 50 %; 95 % confidence interval 25–75 %) and seven patients (44 %) achieved stable disease. Conclusions ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors. Trial registration ClinTrials.gov: NCT0128419

Case studies and evidence-based approaches to addressing urban soil lead contamination

Urban soils in many communities in the United States and internationally have been contaminated by lead (Pb) from past use of lead additives in gasoline, deterioration of exterior paint, emissions from Pb smelters and battery recycling and other industries. Exposure to Pb in soil and related dust is widespread in many inner city areas. Up to 20–40% of urban children in some neighborhoods have blood lead levels (BLLs) equal to or above 5 μg per decilitre, the reference level of health concern by the U.S. Centers for Disease Control. Given the widespread nature of Pb contamination in urban soils it has proven a challenge to reduce exposure. In order to prevent this exposure, an evidence-based approach is required to isolate or remediate the soils and prevent children and adult's ongoing exposure. To date, the majority of community soil Pb remediation efforts have been focused in mining towns or in discrete neighborhoods where Pb smelters have impacted communities. These efforts have usually entailed very expensive dig and dump soil Pb remediation techniques, funded by the point source polluters. Remediating widespread non-point source urban soil contamination using this approach is neither economical nor feasible from a practical standpoint. Despite the need to remediate/isolate urban soils in inner city areas, no deliberate, large scale, cost effective Pb remediation schemes have been implemented to isolate inner city soils impacted from sources other than mines and smelters. However, a city-wide natural experiment of flooding in New Orleans by Hurricane Katrina demonstrated that declines in soil Pb resulted in major BLL reductions. Also a growing body of literature of smaller scale pilot studies and programs does exist regarding low cost efforts to isolate Pb contaminated urban soils. This paper reviews the literature regarding the effectiveness of soil Pb remediation for reducing Pb exposure and BLL in children, and suggests best practices for addressing the epidemics of low-level Pb poisoning occurring in many inner city areas

Towards a Data Sharing Culture: Recommendations for Leadership from Academic Health Centers

Rebecca Crowley and colleagues propose that academic health centers can and should lead the transition towards a culture of biomedical data sharing

Challenging school reform from below: is leadership the missing link in mobilization theory?

This article presents research relating to the experiences of union and community-based campaigns that have sought to challenge the establishment of academy and free schools in England. Such schools are removed from local government control and are seen as a defining element of the neoliberal restructuring of public education. The research draws on social-movement literature, and particularly mobilization theory, to better understand the dynamics of such campaigns and the contexts in which they can either thrive or wither. In the article, I argue that mobilization theory provides a useful framework for such analysis but that it fails to adequately reflect the importance of individual agency and the role of leadership at a local level. Leadership of such campaigns is often assumed by individuals reluctantly, and often defies traditional descriptions of “leadership,” but must be recognized if mobilization theory is to avoid being overly deterministic

Preventing weight gain: the baseline weight related behaviors and delivery of a randomized controlled intervention in community based women

<p>Abstract</p> <p>Background</p> <p>Women aged 25–45 years represent a high risk group for weight gain and those with children are at increased risk because of weight gain associated with pregnancy and subsequent lifestyle change. Average self-reported weight gain is approximately 0.60 kg per year, and weight gain is associated with increased risk of chronic disease. There are barriers to reaching, engaging and delivering lifestyle interventions to prevent weight gain in this population.</p> <p>Methods</p> <p>This study investigated the baseline weight related behaviors and feasibility of recruiting and delivering a low intensity self-management lifestyle intervention to community based women with children in order to prevent weight gain, compared to standard education. The recruitment and delivery of the cluster-randomized controlled intervention was in conjunction with 12 primary (elementary) schools. Baseline data collection included demographic, anthropometric, behavioral and biological measures.</p> <p>Results</p> <p>Two hundred and fifty community based women were randomized as clusters to intervention (n = 127) or control (n = 123). Mean age was 40.4 years (SD 4.7) and mean BMI 27.8 kg/m²(SD 5.6). All components of this intervention were successfully delivered and retention rates were excellent, 97% at 4 months.</p> <p>Nearly all women (90%) reported being dissatisfied with their weight and 72% attempted to self-manage their weight. Women were more confident of changing their diet (mean score 3.2) than physical activity (mean score 2.7). This population perceived they were engaging in prevention behaviors, with 71% reporting actively trying to prevent weight gain, yet they consumed a mean of 68 g fat/day (SD30 g) and 27 g saturated fat/day (SD12 g) representing 32% and 13% of energy respectively. The women had a high rate of dyslipidemia (33%) and engaged in an average of 9187 steps/day (SD 3671).</p> <p>Conclusion</p> <p>Delivery of this low intensity intervention to a broad cross-section of community based women with children is feasible. Women with children are engaging in lifestyle behaviours which do not confer adequate health benefits. They appear to be motivated to attend prevention programs by their interest in weight management. Interventions are required to strengthen and sustain current attempts at achieving healthy lifestyle behaviours in women to prevent weight gain.</p> <p>Trial Registration Number</p> <p>ACTRN 12608000110381</p

Functional cognitive disorder: dementia's blind spot

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalised interventions

Finding Interstellar Particle Impacts on Stardust Aluminium Foils: The Safe Handling, Imaging, and Analysis of Samples Containing Femtogram Residues

Impact ionisation detectors on a suite of spacecraft have shown the direction, velocity, flux and mass distribution of smaller ISP entering the Solar System. During the aphelion segments of the Stardust flight, a dedicated collector surface was oriented to intercept ISP of beta = 1, and returned to Earth in January 2006. In this paper we describe the probable appeareance and size of IS particle craters from initial results of experimental impacts and numerical simulation, explain how foils are being prepared and mounted for crater searching by automated acquisition of high magnification electron images (whilst avoiding contamination of the foils) and comment on appropriate analytical techniques for Preliminary Examination (PE)

Measurements of Flavour Dependent Fragmentation Functions in Z^0 -> qq(bar) Events

Fragmentation functions for charged particles in Z -> qq(bar) events have been measured for bottom (b), charm (c) and light (uds) quarks as well as for all flavours together. The results are based on data recorded between 1990 and 1995 using the OPAL detector at LEP. Event samples with different flavour compositions were formed using reconstructed D* mesons and secondary vertices. The \xi_p = ln(1/x_E) distributions and the position of their maxima \xi_max are also presented separately for uds, c and b quark events. The fragmentation function for b quarks is significantly softer than for uds quarks.Comment: 29 pages, LaTeX, 5 eps figures (and colour figs) included, submitted to Eur. Phys. J.