Proteins unfold in steps

I present results from an experiment on the dynamics of folding of a globular protein (bovine serum albumin). Employing a micro-mechanical technique, I perform the measurements on very few molecules (1–100). I observed a sequence of steps in time for both unfolding and refolding. The overall characteristic time of the process is thus built up of waiting times between successive steps. The pattern of steps is reproducible, demonstrating the existence of deterministic pathways for folding and unfolding. Certain symmetries in the patterns of steps may reflect the architecture of the protein’s structure.

A model of long-term memory storage in the cerebellar cortex: A possible role for plasticity at parallel fiber synapses onto stellate/basket interneurons

By evoking changes in climbing fiber activity, movement errors are thought to modify synapses from parallel fibers onto Purkinje cells (pf*Pkj) so as to improve subsequent motor performance. Theoretical arguments suggest there is an intrinsic tradeoff, however, between motor adaptation and long-term storage. Assuming a baseline rate of motor errors is always present, then repeated performance of any learned movement will generate a series of climbing fiber-mediated corrections. By reshuffling the synaptic weights responsible for any given movement, such corrections will degrade the memories for other learned movements stored in overlapping sets of synapses. The present paper shows that long-term storage can be accomplished by a second site of plasticity at synapses from parallel fibers onto stellate/basket interneurons (pf*St/Bk). Plasticity at pf*St/Bk synapses can be insulated from ongoing fluctuations in climbing fiber activity by assuming that changes in pf*St/Bk synapses occur only after changes in pf*Pkj synapses have built up to a threshold level. Although climbing fiber-dependent plasticity at pf*Pkj synapses allows for the exploration of novel motor strategies in response to changing environmental conditions, plasticity at pf*St/Bk synapses transfers successful strategies to stable long-term storage. To quantify this hypothesis, both sites of plasticity are incorporated into a dynamical model of the cerebellar cortex and its interactions with the inferior olive. When used to simulate idealized motor conditioning trials, the model predicts that plasticity develops first at pf*Pkj synapses, but with additional training is transferred to pf*St/Bk synapses for long-term storage.

What was natural in the coastal oceans?

Humans transformed Western Atlantic coastal marine ecosystems before modern ecological investigations began. Paleoecological, archeological, and historical reconstructions demonstrate incredible losses of large vertebrates and oysters from the entire Atlantic coast. Untold millions of large fishes, sharks, sea turtles, and manatees were removed from the Caribbean in the 17th to 19th centuries. Recent collapses of reef corals and seagrasses are due ultimately to losses of these large consumers as much as to more recent changes in climate, eutrophication, or outbreaks of disease. Overfishing in the 19th century reduced vast beds of oysters in Chesapeake Bay and other estuaries to a few percent of pristine abundances and promoted eutrophication. Mechanized harvesting of bottom fishes like cod set off a series of trophic cascades that eliminated kelp forests and then brought them back again as fishers fished their way down food webs to small invertebrates. Lastly, but most pervasively, mechanized harvesting of the entire continental shelf decimated large, long-lived fishes and destroyed three-dimensional habitats built up by sessile corals, bryozoans, and sponges. The universal pattern of losses demonstrates that no coastal ecosystem is pristine and few wild fisheries are sustainable along the entire Western Atlantic coast. Reconstructions of ecosystems lost only a century or two ago demonstrate attainable goals of establishing large and effective marine reserves if society is willing to pay the costs. Historical reconstructions provide a new scientific framework for manipulative experiments at the ecosystem scale to explore the feasibility and benefits of protection of our living coastal resources.

Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis.

In patients with rheumatoid arthritis the synovial membrane of the affected joint is infiltrated with lymphoid cells which may be arranged in structures resembling germinal centers. We have directly isolated such infiltrates to determine whether B-cell clones within them are selected and expanded in a process analogous to that which normally takes place in the germinal centers in secondary lymphoid organs. The data suggest that an antigen-driven process leads to the accumulation of B cells in the synovial membrane. The finding of identical sequences in consecutive sections suggests that under conditions of chronic stimulation, memory B cells may enter a stage of differentiation in which they proliferate without further accumulation of somatic mutations. Further we see intraclonal diversity which underlines the germinal center-like character of these infiltrates and demonstrates that a microenvironment is built up in this nonlymphoid tissue which supports antigen-dependent differentiation of B cells. This is the first demonstration, to our knowledge, of a germinal center-like reaction outside lymphoid tissue.