Unraveling heme detoxification in the malaria parasite by in situ correlative X-ray fluorescence microscopy and soft X-ray tomography

A key drug target for malaria has been the detoxification pathway of the iron containing molecule heme, which is the toxic byproduct of hemoglobin digestion. The cornerstone of heme detoxification is its sequestration into hemozoin crystals, but how this occurs remains uncertain. We report new results of in vivo rate of heme crystallization in the malaria parasite, based on a new technique to measure element specific concentrations at defined locations in cell ultrastructure. Specifically, a high resolution correlative combination of cryo soft X ray tomography has been developed to obtain 3D parasite ultrastructure with cryo X ray fluorescence microscopy to measure heme concentrations. Our results are consistent with a model for crystallization via the heme detoxification protein. Our measurements also demonstrate the presence of considerable amounts of non crystalline heme in the digestive vacuole, which we show is most likely contained in hemoglobin. These results suggest a tight coupling between hemoglobin digestion and heme crystallization, highlighting a new link in the crystallization pathway for drug developmen

Short-term organoid culture for drug sensitivity testing of high-grade serous carcinoma.

ObjectiveCancer patient-derived organoids (PDOs) grow as three dimensional (3D) structures in the presence of extracellular matrix and have been found to represent the original tumor's genetic complexity. In addition, PDOs can be grown and subjected to drug sensitivity testing in a shorter time course and with lesser expense than patient-derived xenograft models. Many patients with recurrent ovarian cancer develop malignant effusions that become refractory to chemotherapy. Since these same patients often present for palliative aspiration of ascites or pleural effusions, there is a potential opportunity to obtain tumor specimens in the form of multicellular spheroids (MCS) present in malignant effusion fluids. Our objective was to develop a short duration culture of MCS from ovarian cancer malignant effusions in conditions selected to support organoid growth and use them as a platform for empirical drug sensitivity testing.MethodsIn this study, malignant effusion specimens were collected from patients with high-grade serous ovarian carcinoma (HGSOC). MCS were recovered and subjected to culture conditions designed to support organoid growth. In a subset of specimens, RNA-sequencing was performed at two time points during the short-term culture to determine changes in transcriptome in response to culture conditions. Organoid induction was also characterized in these specimens using Ki67 staining and histologic analysis. Drug sensitivity testing was performed on all specimens.ResultsOur model describes organoids formed within days of primary culture, which can recapitulate the histological features of malignant ascites fluid and can be expanded for at least 6 days. RNA-seq analysis of four patient specimens showed that within 6 days of culture, there was significant up-regulation of genes related to cellular proliferation, epithelial-mesenchymal transition, and KRAS signaling pathways. Drug sensitivity testing identified several agents with therapeutic potential.ConclusionsShort duration organoid culture of MCS from HGSOC malignant effusions can be used as a platform for empiric drug sensitivity testing. These ex vivo models may be helpful in screening new or existing therapeutic agents prior to individualized treatment options

Ovarian cancer in younger vs older women: a population-based analysis

To compare the clinico-pathologic prognostic factors and survival of younger vs older women diagnosed with epithelial ovarian cancer. Demographic, clinico-pathologic, treatment, and surgery information were obtained from patients with ovarian cancer from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001 and analysed using Kaplan–Meier estimates. Of 28 165 patients, 400 were <30 years (very young), 11 601 were 30–60 (young), and 16 164 were >60 (older) years of age. Of the very young, young, and older patients, 261 (65.3%), 4664 (40.2%), and 3643 (22.5%) had stage I–II disease, respectively (P<0.001). Across all stages, very young women had a significant survival advantage over the young and older groups with 5-year disease-specific survival estimates at 78.8% vs 58.8 and 35.3%, respectively (P<0.001). This survival difference between the age groups persists even after adjusting for race, stage, grade, and surgical treatment. Reproductive age (16–40 years) women with stage I–II epithelial ovarian cancer who received uterine-sparing procedures had similar survivals compared to those who underwent standard surgery (93.3% vs 91.5%, P=0.26). Younger women with epithelial ovarian cancer have a survival advantage compared to older patients

Prospects for radical emissions reduction through behaviour and lifestyle change

Over the past two decades, scholars and practitioners across the social sciences, in policy and beyond have proposed, trialled and developed a wide range of theoretical and practical approaches designed to bring about changes in behaviours and lifestyles that contribute to climate change. With the exception of the establishment of a small number of iconic behaviours such as recycling, it has however proved extremely difficult to bring about meaningful transformations in personal greenhouse gas emissions at either the individual or societal level, with multiple reviews now pointing to the limited efficacy of current approaches. We argue that the majority of approaches designed to achieve mitigation have been constrained by the need to operate within prevailing social scientific, economic and political orthodoxies which have precluded the possibility of non-marginal change. In this paper we ask what a truly radical approach to reducing personal emissions would look like from social science perspectives which challenge the unstated assumptions severely limiting action to date, and which explore new alternatives for change. We emphasise the difficulties likely to impede the instituting of genuinely radical societal change regarding climate change mitigation, whilst proposing ways that the ground could be prepared for such a transformation to take place

Evolution of opinions on social networks in the presence of competing committed groups

Public opinion is often affected by the presence of committed groups of individuals dedicated to competing points of view. Using a model of pairwise social influence, we study how the presence of such groups within social networks affects the outcome and the speed of evolution of the overall opinion on the network. Earlier work indicated that a single committed group within a dense social network can cause the entire network to quickly adopt the group's opinion (in times scaling logarithmically with the network size), so long as the committed group constitutes more than about 10% of the population (with the findings being qualitatively similar for sparse networks as well). Here we study the more general case of opinion evolution when two groups committed to distinct, competing opinions $A$ and $B$, and constituting fractions $p_A$ and $p_B$ of the total population respectively, are present in the network. We show for stylized social networks (including Erd\H{o}s-R\'enyi random graphs and Barab\'asi-Albert scale-free networks) that the phase diagram of this system in parameter space $(p_A,p_B)$ consists of two regions, one where two stable steady-states coexist, and the remaining where only a single stable steady-state exists. These two regions are separated by two fold-bifurcation (spinodal) lines which meet tangentially and terminate at a cusp (critical point). We provide further insights to the phase diagram and to the nature of the underlying phase transitions by investigating the model on infinite (mean-field limit), finite complete graphs and finite sparse networks. For the latter case, we also derive the scaling exponent associated with the exponential growth of switching times as a function of the distance from the critical point.Comment: 23 pages: 15 pages + 7 figures (main text), 8 pages + 1 figure + 1 table (supplementary info

Examining user comments for deliberative democracy: a corpus-driven analysis of the climate change debate online

The public perception of climate change is characterized by heterogeneity, even polarization. Deliberative discussion is regarded by some as key to overcoming polarization and engaging various publics with the complex issue of climate change. In this context, online engagement with news stories is seen as a space for a new “deliberative democratic potential” to emerge. This article examines aspects of deliberation in user comment threads in response to articles on climate change taken from the Guardian. “Deliberation” is understood through the concepts “reciprocity”, “topicality”, and “argumentation”. We demonstrate how corpus analysis can be used to examine the ways in which online debates around climate change may create or deny opportunities for multiple voices and deliberation. Results show that whilst some aspects of online discourse discourage alternative viewpoints and demonstrate “incivility”, user comments also show potential for engaging in dialog, and for high levels of interaction

Climate change and climate variability: personal motivation for adaptation and mitigation

BACKGROUND: Global climate change impacts on human and natural systems are predicted to be severe, far reaching, and to affect the most physically and economically vulnerable disproportionately. Society can respond to these threats through two strategies: mitigation and adaptation. Industry, commerce, and government play indispensable roles in these actions but so do individuals, if they are receptive to behavior change. We explored whether the health frame can be used as a context to motivate behavioral reductions of greenhouse gas emissions and adaptation measures. METHODS: In 2008, we conducted a cross-sectional survey in the United States using random digit dialing. Personal relevance of climate change from health threats was explored with the Health Belief Model (HBM) as a conceptual frame and analyzed through logistic regressions and path analysis. RESULTS: Of 771 individuals surveyed, 81% (n = 622) acknowledged that climate change was occurring, and were aware of the associated ecologic and human health risks. Respondents reported reduced energy consumption if they believed climate change could affect their way of life (perceived susceptibility), Odds Ratio (OR) = 2.4 (95% Confidence Interval (CI): 1.4-4.0), endanger their life (perceived severity), OR = 1.9 (95% CI: 1.1-3.1), or saw serious barriers to protecting themselves from climate change, OR = 2.1 (95% CI: 1.2-3.5). Perceived susceptibility had the strongest effect on reduced energy consumption, either directly or indirectly via perceived severity. Those that reported having the necessary information to prepare for climate change impacts were more likely to have an emergency kit OR = 2.1 (95% CI: 1.4-3.1) or plan, OR = 2.2 (95% CI: 1.5-3.2) for their household, but also saw serious barriers to protecting themselves from climate change or climate variability, either by having an emergency kit OR = 1.6 (95% CI: 1.1-2.4) or an emergency plan OR = 1.5 (95%CI: 1.0-2.2). CONCLUSIONS: Motivation for voluntary mitigation is mostly dependent on perceived susceptibility to threats and severity of climate change or climate variability impacts, whereas adaptation is largely dependent on the availability of information relevant to climate change. Thus, the climate change discourse could be framed from a health perspective to motivate behaviour change

Communicating climate change: conduits, content, and consensus

Climate change has been the subject of increasing efforts by scientists to understand its causes and implications; it has been of growing interest to policymakers, international bodies, and a variety of nongovernment organizations; and it has attracted varied amounts of attention from traditional and, increasingly, online media. These developments have been aligned with shifts in the nature of climate change communication, with changes in how researchers study it and how a variety of actors try to influence it. This article situates the theory and practice of climate change communication within developments that have taken place since we first reviewed the field in 2009. These include the rise of new social media conduits for communication, research, and practice aimed at fine tuning communication content, and the rise to prominence of scientific consensus as part of that content. We focus in particular on continuing tensions between a focus on the part of communicators to inform the public and more dialogic strategies of public engagement. We also consider the tension between efforts to promote consensus and certainty in climate science and approaches that attempt to engage with uncertainty more fully. We explore the lessons to be learnt from climate communication since 2009, highlighting how the field remains haunted by the deficit model of science communication. Finally, we point to more fruitful future directions for climate change communication, including more participatory models that acknowledge, rather than ignore, residual uncertainties in climate science in order to stimulate debate and deliberation

Climate Change and Local Public Health in the United States: Preparedness, Programs and Perceptions of Local Public Health Department Directors

While climate change is inherently a global problem, its public health impacts will be experienced most acutely at the local and regional level, with some jurisdictions likely to be more burdened than others. The public health infrastructure in the U.S. is organized largely as an interlocking set of public agencies at the federal, state and local level, with lead responsibility for each city or county often residing at the local level. To understand how directors of local public health departments view and are responding to climate change as a public health issue, we conducted a telephone survey with 133 randomly selected local health department directors, representing a 61% response rate. A majority of respondents perceived climate change to be a problem in their jurisdiction, a problem they viewed as likely to become more common or severe over the next 20 years. Only a small minority of respondents, however, had yet made climate change adaptation or prevention a top priority for their health department. This discrepancy between problem recognition and programmatic responses may be due, in part, to several factors: most respondents felt personnel in their health department–and other key stakeholders in their community–had a lack of knowledge about climate change; relatively few respondents felt their own health department, their state health department, or the Centers for Disease Control and Prevention had the necessary expertise to help them create an effective mitigation or adaptation plan for their jurisdiction; and most respondents felt that their health department needed additional funding, staff and staff training to respond effectively to climate change. These data make clear that climate change adaptation and prevention are not currently major activities at most health departments, and that most, if not all, local health departments will require assistance in making this transition. We conclude by making the case that, through their words and actions, local health departments and their staff can and should play a role in alerting members of their community about the prospect of public health impacts from climate change in their jurisdiction

Understanding the (non-)Use of Societal Wellbeing Indicators in National Policy Development : What Can We Learn from Civil Servants? A UK Case Study

Gross Domestic Product is often used as a proxy for societal well-being in the context of policy development. Its shortcomings in this context are, however, well documented, and numerous alternative indicator sets have been developed. Despite this, there is limited evidence of widespread use of these alternative indicator sets by people working in policy areas relevant to societal wellbeing. Civil servants are an important group of indicator end-users. Better understanding their views concerning measuring societal wellbeing can support wider discussions about what factors determine indicator use and influence in policy decision-making. Taking the UK as a case study, we ask what views exist among civil servants in the UK about measuring societal well-being? To answer this question, we used a bootstrapped Q methodology, interviewing 20 civil servants to elicit their views about measuring societal well-being. Three distinct discourses emerged from our analysis: one that was concerned about the consequences of ignoring natural, social and human capital in decision making; one that emphasised opportunity and autonomy as key determinants of well-being; and one that focused on the technical aspects of measuring societal well-being. Each of these discourses has direct implications for the way that we integrate societal wellbeing into policy making and highlights the potential benefits of including end-users in indicator development and strategy