The Macrophage Inhibitor CNI-1493 Blocks Metastasis in a Mouse Model of Ewing Sarcoma through Inhibition of Extravasation

Metastatic Ewing Sarcoma carries a poor prognosis, and novel therapeutics to prevent and treat metastatic disease are greatly needed. Recent evidence demonstrates that tumor-associated macrophages in Ewing Sarcoma are associated with more advanced disease. While some macrophage phenotypes (M1) exhibit anti-tumor activity, distinct phenotypes (M2) may contribute to malignant progression and metastasis. In this study, we show that M2 macrophages promote Ewing Sarcoma invasion and extravasation, pointing to a potential target of anti-metastatic therapy. CNI-1493 is a selective inhibitor of macrophage function and has shown to be safe in clinical trials as an anti-inflammatory agent. In a xenograft mouse model of metastatic Ewing Sarcoma, CNI-1493 treatment dramatically reduces metastatic tumor burden. Furthermore, metastases in treated animals have a less invasive morphology. We show in vitro that CNI-1493 decreases M2-stimulated Ewing Sarcoma tumor cell invasion and extravasation, offering a functional mechanism through which CNI-1493 attenuates metastasis. These data indicate that CNI-1493 may be a safe and effective adjuvant agent for the prevention and treatment of metastatic Ewing Sarcoma.     

Neuroactive hormones and interpersonal trust: International evidence

Social attachment is vital for human health and welfare. Recent experimental evidence in humans has identified the role of neuroactive hormones, especially the peptide oxytocin, in mediating trusting behaviors. Herein, we test if the endocrinological basis for trust between humans scales up to the country level. Trust pervades nearly every aspect of our daily lives, yet survey data on trust show substantial variation across countries. Using 31 measures of biological, social, and environmental factors associated with hormone levels for a sample of 41 countries, we find that two classes of factors are related to trust: consumption of plant-based estrogens (phytoestrogens), and the presence of environmental conditions that include measures of estrogen-like molecules. Our findings provide preliminary evidence that interpersonal trust at the country level may be related to the intake of neuroactive hormones.     

The Harm of Bioethics: A Critique of Singer and Callahan on Obesity

Debate concerning the social impact of obesity has been ongoing since at least the 1980s. Bioethicists, however, have been relatively silent. If obesity is addressed it tends to be in the context of resource allocation or clinical procedures such as bariatric surgery. However, prominent bioethicists Peter Singer and Dan Callahan have recently entered the obesity debate to argue that obesity is not simply a clinical or personal issue but an ethical issue with social and political consequences. This article critically examines two problematic aspects of Singer and Callahan's respective approaches. First, there is an uncritical assumption that individuals are autonomous agents responsible for health‐related effects associated with food choices. In their view, individuals are obese because they choose certain foods or refrain from physical activity. However, this view alone does not justify intervention. Both Singer and Callahan recognize that individuals are free to make foolish choices so long as they do not harm others. It is at this point that the second problematic aspect arises. To interfere legitimately in the liberty of individuals, they invoke the harm principle. I contend, however, that in making this move both Singer and Callahan rely on superficial readings of public health research to amplify the harm caused by obese individuals and ignore pertinent epidemiological research on the social determinants of obesity. I argue that the mobilization of the harm principle and corresponding focus on individual behaviours without careful consideration of the empirical research is itself a form of harm that needs to be taken seriously.     

Oxygen: a master regulator of pancreatic development?

Beyond its role as an electron acceptor in aerobic respiration, oxygen is also a key effector of many developmental events. The oxygen‐sensing machinery and the very fabric of cell identity and function have been shown to be deeply intertwined. Here we take a first look at how oxygen might lie at the crossroads of at least two of the major molecular pathways that shape pancreatic development. Based on recent evidence and a thorough review of the literature, we present a theoretical model whereby evolving oxygen tensions might choreograph to a large extent the sequence of molecular events resulting in the development of the organ. In particular, we propose that lower oxygenation prior to the expansion of the vasculature may favour HIF (hypoxia inducible factor)‐mediated activation of Notch and repression of Wnt/β‐catenin signalling, limiting endocrine cell differentiation. With the development of vasculature and improved oxygen delivery to the developing organ, HIF‐mediated support for Notch signalling may decline while the β‐catenin‐directed Wnt signalling is favoured, which would support endocrine cell differentiation and perhaps exocrine cell proliferation/differentiation.     

A Temporally Explicit Production Efficiency Model for Fuel Load Allocation in Southern Africa

Abstract We present a regional fuel load model (1 km² spatial resolution) applied in the southern African savanna region. The model is based on a patch-scale production efficiency model (PEM) scaled up to the regional level using empirical relationships between patch-scale behavior and multi-source remote sensing data (spatio-temporal variability of vegetation and climatic variables). The model requires the spatial distribution of woody vegetation cover, which is used to determine separate respiration rates for tree and grass. Net primary production, grass and tree leaf death, and herbivory are also taken into account in this mechanistic modeling approach. The fuel load model has been calibrated and validated from independent measurements taken from savanna vegetation in Africa southward from the equator. A sensitivity analysis on the effect of climate variables (incoming radiation, air temperature, and precipitation) has been conducted to demonstrate the strong role that water availability has in determining productivity and subsequent fuel load over the southern African region. The model performance has been tested in four different areas representative of a regional increasing rainfall gradient—Etosha National Park, Namibia, Mongu and Kasama, Zambia, as well as in Kruger National Park, South Africa. Within each area, we analyze model output from three different magnitudes of canopy coverage (<5, 30, and 50%). We find that fuel load ranges predicted by the model are globally in agreement with field measurements for the same year. High rainfall sustains green herbaceous production late in the dry season and delays tree leaf litter production. Effect of water on production varies across the rainfall gradient with delayed start of green material production in more arid regions.     

Über die Untersuchungen von A. H. Blaauw,betreffend die Beziehung zwischen Lichtintensität und Beleuchtungsdauer bei der phototropischen Krümmung von Keimlingen vonAvena sativa

Ohne ZusammenfassungProceedings of the Meetings of Saturday September 26, 1908.Die vorliegende Übersetzung, zu der Herr Prof. Went mich gütigst autorisierte, rechtfertigt sich durch die in theoretischer, ganz besonders aber in methodologischer Hinsicht überaus wichtigen Ergebnisse Blaauws. Die Untersuchung bestätigt zunächst ein Gesetz, das der Übersetzer für die Abhängigkeit der Präsentationszeit von der Lichtintensität festgestellt hat (die diesbezügliche Abhandlung war Herrn Prof. Went zur Zeit, als er dieses Referat schrieb, noch nicht zu Gesicht gekommen), verfolgt aber diese Gesetzmäßigkeit innerhalb wesentlich weiterer Grenzen. Die Feststellung ganz besonders, daß bei entsprechend intensiver Beleuchtung die Präsentationszeit bis auf 1/1000 Sekunde sinkt, zusammengehalten mit den Tatsachen der feinen Unterschiedsempfind-lichkeit der Pflanzen (Wiesner) und der außerordentlich kurzen Perzeptions-zeit (Fitting), muß die reizphysiologische Methodik reformieren und sie zu ebenso exaktem Arbeiten anspornen, wie es bei psychophysischen Experimenten längst der Fall ist.     

The impossible coincidence. A single‐species model for the origins of modern human behavior in Europe

Few topics in palaeoanthropology have generated more recent debate than the nature and causes of the remarkable transformation in human behavioral patterns that marked the transition from the Middle to the Upper Paleolithic in Europe. 1 - 11 Those of us who have argued for an effective technological and cultural “revolution” at this point in the Paleolithic sequence have emphasized three main dimensions 1 , 2 , 9 , 11 - 14 : the wide range of different aspects of behavior that appear to have been affected (Fig. 1); the relative speed and abruptness with which most of these changes can be documented in the archeological records from the different regions of Europe; and the potentially profound social and cognitive implications of many of the innovations involved. Most striking of all in this context is the abrupt appearance and proliferation of various forms of perforated animal teeth, shells, beads, and other personal ornaments, and the even more dramatic eruption of remarkably varied and sophisticated forms of art, ranging from representations of male and female sex organs, through the highly stylized animal and combined animal‐human figures from southern Germany, to the striking wall paintings of the Chauvet Cave. 8 , 15 - 18 One might add to this the similar proliferation of more enigmatic but potentially equally significant abstract “notation” systems on bone and ivory artifacts. 19 To describe the Upper Paleolithic revolution in Europe as reflecting preeminently an explosion in explicitly symbolic behavior and expression is in no sense an exaggeration, as most prehistorians would now agree. We are probably on safe ground in assuming that symbolic behavior and expression of this level of complexity would be inconceivable in the absence of highly structured language systems and brains closely similar, if not identical to, our own. 5 , 17 , 20 - 28 .     

Long-term memory modules

One particular kind of structure offers possible explanations, for long-term memory, efficient consolidation of stored information from the environment, clustering of data strings and multimodal functioning. It is a possible model for pieces of neural structure and its use offers a uniform method for both studying and constructing an extensive class of mechanisms.