RAB-6.1 and RAB-6.2 Promote Retrograde Transport in C. elegans

Retrograde transport is a critical mechanism for recycling certain membrane cargo. Following endocytosis from the plasma membrane, retrograde cargo is moved from early endosomes to Golgi followed by transport (recycling) back to the plasma membrane. The complete molecular and cellular mechanisms of retrograde transport remain unclear. The small GTPase RAB-6.2 mediates the retrograde recycling of the AMPA-type glutamate receptor (AMPAR) subunit GLR-1 in C. elegans neurons. Here we show that RAB-6.2 and a close paralog, RAB-6.1, together regulate retrograde transport in both neurons and non-neuronal tissue. Mutants for rab-6.1 or rab-6.2 fail to recycle GLR-1 receptors, resulting in GLR-1 turnover and behavioral defects indicative of diminished GLR-1 function. Loss of both rab-6.1 and rab-6.2 results in an additive effect on GLR-1 retrograde recycling, indicating that these two C. elegans Rab6 isoforms have overlapping functions. MIG-14 (Wntless) protein, which undergoes retrograde recycling, undergoes a similar degradation in intestinal epithelia in both rab-6.1 and rab-6.2 mutants, suggesting a broader role for these proteins in retrograde transport. Surprisingly, MIG-14 is localized to separate, spatially segregated endosomal compartments in rab-6.1 mutants compared to rab-6.2 mutants. Our results indicate that RAB-6.1 and RAB-6.2 have partially redundant functions in overall retrograde transport, but also have their own unique cellular- and subcellular functions.     

Field Measurements Indicate Unexpected,Serious Underestimation of Mussel Heart Rates and Thermal Tolerance by Laboratory Studies

Attempts to predict the response of species to long-term environmental change are generally based on extrapolations from laboratory experiments that inevitably simplify the complex interacting effects that occur in the field. We recorded heart rates of two genetic lineages of the brown mussel Perna perna over a full tidal cycle in-situ at two different sites in order to evaluate the cardiac responses of the two genetic lineages present on the South African coast to temperature and the immersion/emersion cycle. “Robomussel” temperature loggers were used to monitor thermal conditions at the two sites over one year. Comparison with live animals showed that robomussels provided a good estimate of mussel body temperatures. A significant difference in estimated body temperatures was observed between the sites and the results showed that, under natural conditions, temperatures regularly approach or exceed the thermal limits of P. perna identified in the laboratory. The two P. perna lineages showed similar tidal and diel patterns of heart rate, with higher cardiac activity during daytime immersion and minimal values during daytime emersion. Comparison of the heart rates measured in the field with data previously measured in the laboratory indicates that laboratory results seriously underestimate heart rate activity, by as much as 75%, especially during immersion. Unexpectedly, field estimates of body temperatures indicated an ability to tolerate temperatures considered lethal on the basis of laboratory measurements. This suggests that the interaction of abiotic conditions in the field does not necessarily raise vulnerability to high temperatures.     

THE ZOOSPORE OF CHLOROKYBUS ATMOPHYTICUS,A CHAROPHYTE WITH SARCINOID GROWTH HABIT

Chlorokybus atmophyticus has a sarcinoid growth habit and produces scale-covered zoospores. Flagella are laterally inserted and attached internally to a multilayered structure characteristic of the Charophyceae. There are two kinds of pyrenoid in each cell, a feature previously observed in only one scaly green flagellate. C. atmophyticus demonstrates that the sarcinoid growth habit arose independently at least twice in the green algae and cannot be used to define taxonomic groups unless combined with other criteria. It is further concluded that C. atmophyticus should be classified in a separate family Chlorokybaceae and a separate order Chloroky bales.     

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.     

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.