In This Issue
APPLIED PHYSICAL SCIENCES, CELL BIOLOGY
Microfabricated stencils aid studies of cell movement
Cell migration plays a critical role in many physiological processes including embryonic development, immune response, and wound healing. Although some cells dissociate individually to explore their surroundings, others migrate en masse and invade an open area together, maintaining tight intracellular contacts. In conventional in vitro migration experiments, so called “scratch-wounding” assays, cells are mechanically removed from a monolayer by a pipette tip or razor blade. These techniques destroy many cells, leave border cells permeable and porous, and make it difficult to distinguish injury-recovery mechanisms from ones involved in motility. Mathieu Poujade et al. have developed a technique for studying cell migration that leaves confluent layers intact and encourages natural cellular movement. They plated a canine kidney cell line onto microfabricated elastic stencils with rectangular openings. After the cells reached confluence, the authors peeled off the stencil, freeing the cells to move across the gaps. The presence of free surface was enough to stimulate cell migration via coordinated displacements within a monolayer. Leader cells, temporarily shedding their epithelial character, propelled themselves across the open surfaces and made finger-like projections that terminated when they reached another population of cells. Human growth factor, which at low concentrations accelerates healing, promoted cell motility in this system but suppressed the “fingering” behavior of leader cells. — F.A.
Collectively migrating epithelial cells triggered by free surface.
“Collective migration of an epithelial monolayer in response to a model wound” by M. Poujade, E. Grasland-Mongrain, A. Hertzog, J. Jouanneau, P. Chavrier, B. Ladoux, A. Buguin, and P. Silberzan (see pages 15988–15993)
BIOPHYSICS
Molecular evolution and organism fitness linked to protein folding
Recent advances in genomics and bioinformatics have spurred the study of molecular evolution. However, a fundamental assumption of the field has not changed: that certain alleles confer a selective advantage. An explicit link has been missing between the fitness or reproductive success of organisms and the molecular properties of proteins encoded by their genomes, even as an understanding of protein folding, stability, and function has grown. Konstantin Zeldovich et al. developed an evolutionary model where an organism's fitness can be inferred from its DNA sequence using a protein folding model. They based their calculations on a fundamental relationship between genotype and phenotype: For an organism to survive, all of its essential genes must encode proteins with at least minimal stability. The authors' theory relates mutation rate, genome size, and thermodynamic response of essential proteins to genomic point mutations. Mesophiles, organisms that thrive at moderate temperatures, will go extinct when their mutation rate exceeds six per essential part of the genome per generation. That barrier is lower for thermophiles, at just two. The authors' work has broad implications for our understanding of the origins of life, the creation of artificial life, the design of mutation-inducing drugs, and radiation therapy. — F.A.
Evolution as a constrained diffusion in the protein stability space.
“Protein stability imposes limits on organism complexity and speed of molecular evolution” by Konstantin B. Zeldovich, Peiqiu Chen, and Eugene I. Shakhnovich (see pages 16152–16157)
ENVIRONMENTAL SCIENCES
Warm response to the Little Ice Age
The Little Ice Age of the mid-14th to 19th centuries is infamous for spawning crop failures, famine, and epidemic disease throughout Europe, but the effects of this global cooling event in other parts of the world are not well defined. To determine the response of tropical vegetation to the cooling events of the Little Ice Age in Mesoamerica, Ma. del Socorro Lozano-Garcia et al. reconstructed climate and vegetation history during the last 2,000 years from sediment records from a lake in the Sierra de Los Tuxtlas region in south-central Mexico. The period saw the deepest lake in two millennia, with the deepest lake phases linked to periods of minimum solar activity, suggesting that solar forcing is an important element in tropical responses to climate change. In addition, the Little Ice Age produced the densest tropical forest cover, which the authors attribute to a moderate winter cooling, shorter dry seasons, and increased winter precipitation. The findings suggest that seasonal responses may offer insights for assessing the impacts of recent climate change. — M.M.
“Tracing the effects of the Little Ice Age in the tropical lowlands of eastern Mesoamerica” by Ma. del Socorro Lozano-García, Margarita Caballero, Beatriz Ortega, Alejandro Rodríguez, and Susana Sosa (see pages 16200–16203)
NEUROSCIENCE
Anorexia and Ecstasy share pathway
Anorexia nervosa can turn deadly as the sufferer deprives the body of calories it needs, but the neuronal signaling faults that lead toappetite suppression are unknown. Alexandra Jean et al. explored the molecular mechanisms behind anorexia and discovered similarities to appetite suppression induced by the drug Ecstasy, or MDMA. MDMA mimics the appetite loss characteristic of anorexia. The authors surmised that these effects might be centered in the nucleus accumbens, one of the brain's reward centers. This area has a high concentration of the serotonin receptor subset 5-HT4R, which has been implicated in decreased food intake. Stimulating the receptor in mice reduced their drive to eat and increased production of the same transcripts stimulated in response to cocaine and amphetamines. Blocking the receptor with RNA interference increased food intake. Mice lacking the 5-HT4 receptor were less sensitive to the appetite-suppressant effects of ecstasy. In addition to determining how MDMA exerts one of its effects, the authors show that appetite regulation associated with anorexia occurs in a region of the brain other than the hypothalamus. — T.H.D.
5-HT4R-mediated upregulation triggers the appetite-suppressant effects of MDMA.
“Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens” by Alexandra Jean, Grégory Conductier, Christine Manrique, Constantin Bouras, Philippe Berta, René Hen, Yves Charnay, Joël Bockaert, and Valérie Compan (see pages 16335–16340)
