The likelihood with which an action potential elicits neurotransmitter release, the release probability (p r ), is an important component of synaptic strength. Regulatory mechanisms controlling several steps of synaptic vesicle (SV) exocytosis may affect p r , yet their relative importance in determining p r and eliciting temporal changes in neurotransmitter release at individual synapses is largely unknown. We have investigated whether the size of the active zone cytomatrix is a major determinant of p r and whether changes in its size lead to corresponding alterations in neurotransmitter release. We have used a fluorescent sensor of SV exocytosis, synaptophysin-pHluorin, to measure p r at individual synapses with high accuracy and employed a fluorescently labeled cytomatrix protein, Bassoon, to quantify the amount of active zone cytomatrix present at these synapses. We find that, for synapses made by a visually identified presynaptic neuron, p r is indeed strongly correlated with the amount of active zone cytomatrix present at the presynaptic specialization. Intriguingly, active zone cytomatrices are frequently subject to synapse-specific changes in size on a time scale of minutes. These spontaneous alterations in active zone size are associated with corresponding changes in neurotransmitter release. Our results suggest that the size of the active zone cytomatrix has a large influence on the reliability of synaptic transmission. Furthermore, they implicate mechanisms leading to rapid structural alterations at active zones in synapse-specific forms of plasticity. release probability | synaptic vesicle docking | active zone cytomatrix | plasticity | pHluorin S ynaptic transmission between most neurons is unreliable as a presynaptic action potential elicits neurotransmitter (NT) release at any individual synapse with a release probability (p r ) of less than one. This probability can vary considerably among synapses of the same axon, often in a target-specific manner (1-3). Similarly, synapses onto a single neuron often display widely varying release probabilities (4-7). Moreover, p r can undergo sustained activity-dependent changes over time (8)(9)(10)(11). These observations suggest that p r is an important determinant of synaptic strength that is tightly controlled by the presynaptic neuron and/or, indirectly, by its postsynaptic target.Although numerous studies have highlighted specific regulatory mechanisms affecting p r of synapses at rest, a concise picture of how p r at individual synapses is determined is only beginning to emerge. Synaptic vesicle (SV) exocytosis is a multistep process during which SVs have to dock at the active zone cytomatrix and undergo a priming step before they are "readily releasable," i.e., immediately available for fusion with the plasma membrane in response to calcium influx through voltage-gated calcium channels (12). Evidence that the size of a synapse's readily releasable pool (RRP) of SVs is closely correlated with its p r (7, 13) suggests that p r is mainly determined by pro...

Understanding the patellofemoral joint in total knee arthroplasty P atellofemoral complications historically have contributed up to 50% of revision surgery. 1 With modern design refinements and improved techniques, the burden of revision from patellofemoral complications is less than it was previously; however, these complications remain some of the most challenging problems in knee arthroplasty. Complications involving the patellofemoral joint (PFJ) can occur with both resurfaced and nonresurfaced patellae. In resurfaced patellae, complications include patellar maltracking, fracture, avascular necrosis, clunk and anterior knee pain. In knees with nonresurfaced patellae, some of the same complications can take place, such as maltracking, clunk,

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The NIH Genomic Data Sharing Policy, effective in January 2015, encourages researchers to obtain broad consent to share data for unspecified biomedical research. The ethics of extensive data sharing depend in part on study participants’ understanding of the risks and benefits. Interviews with participants in the Personal Genome Project show that study participants can readily discuss the risks, including loss of privacy, and are willing to accept risks because they value the opportunity to contribute to health science. They have expansive views of the benefits for science, medicine, and their own health and curiosity. With justice in mind, further exploration is needed to evaluate consent for data sharing among more diverse and vulnerable populations.

Potential donors were risk takers and were willing to donate when given the opportunity. They accepted significant risks, especially if they had a close emotional relationship with the recipient.