Synaptotagmin-1 is the Ca2+ sensor for fast striatal dopamine release.

Dopamine powerfully controls neural circuits through neuromodulation. In the vertebrate striatum, dopamine adjusts cellular functions to regulate behaviors across broad time scales, but how the dopamine secretory system is built to support fast and slow neuromodulation is not known. Here, we set out to identify Ca2+-triggering mechanisms for dopamine release. We find that synchronous dopamine secretion is abolished in acute brain slices of conditional knockout mice in which Synaptotagmin-1 is removed from dopamine neurons. This indicates that Synaptotagmin-1 is the Ca2+ sensor for fast dopamine release. Remarkably, dopamine release induced by strong depolarization and asynchronous release during stimulus trains are unaffected by Synaptotagmin-1 knockout. Microdialysis further reveals that these modes and action potential-independent release provide significant amounts of extracellular dopamine in vivo. We propose that the molecular machinery for dopamine secretion has evolved to support fast and slow signaling modes, with fast release requiring the Ca2+ sensor Synaptotagmin-1.

Design and Study of a Next-Generation Computer-Assisted System for Transoral Laser Microsurgery.

OBJECTIVE: To present a new computer-assisted system for improved usability, intuitiveness, efficiency, and controllability in transoral laser microsurgery (TLM). STUDY DESIGN: Pilot technology feasibility study. SETTING: A dedicated room with a simulated TLM surgical setup: surgical microscope, surgical laser system, instruments, ex vivo pig larynxes, and computer-assisted system. SUBJECTS AND METHODS: The computer-assisted laser microsurgery (CALM) system consists of a novel motorized laser micromanipulator and a tablet- and stylus-based control interface. The system setup includes the Leica 2 surgical microscope and the DEKA HiScan Surgical laser system. The system was validated through a first-of-its-kind observational study with 57 international surgeons with varied experience in TLM. The subjects performed real surgical tasks on ex vivo pig larynxes in a simulated TLM scenario. The qualitative aspects were established with a newly devised questionnaire assessing the usability, efficiency, and suitability of the system. RESULTS: The surgeons evaluated the CALM system with an average score of 6.29 (out of 7) in ease of use and ease of learning, while an average score of 5.96 was assigned for controllability and safety. A score of 1.51 indicated reduced workload for the subjects. Of 57 subjects, 41 stated that the CALM system allows better surgical quality than the existing TLM systems. CONCLUSIONS: The CALM system augments the usability, controllability, and efficiency in TLM. It enhances the ergonomics and accuracy beyond the current state of the art, potentially improving the surgical safety and quality. The system offers the intraoperative automated scanning of customized long incisions achieving uniform resections at the surgical site.

ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons.

Interfaces between organelles are emerging as critical platforms for many biological responses in eukaryotic cells. In yeast, the ERMES complex is an endoplasmic reticulum (ER)-mitochondria tether composed of four proteins, three of which contain a SMP (synaptotagmin-like mitochondrial-lipid binding protein) domain. No functional ortholog for any ERMES protein has been identified in metazoans. Here, we identified PDZD8 as an ER protein present at ER-mitochondria contacts. The SMP domain of PDZD8 is functionally orthologous to the SMP domain found in yeast Mmm1. PDZD8 was necessary for the formation of ER-mitochondria contacts in mammalian cells. In neurons, PDZD8 was required for calcium ion (Ca2+) uptake by mitochondria after synaptically induced Ca2+-release from ER and thereby regulated cytoplasmic Ca2+ dynamics. Thus, PDZD8 represents a critical ER-mitochondria tethering protein in metazoans. We suggest that ER-mitochondria coupling is involved in the regulation of dendritic Ca2+ dynamics in mammalian neurons.

A real-time and reduced-complexity approach to the detection and monitoring of static joint overloading in humans.

This paper proposes a novel technique for the real-time estimation of the joint torques variations in humans while performing heavy manipulation tasks. To achieve this, the method is based on the deviations of the Centre of Pressure (CoP) and Ground Reaction Force (GRF) in the presence of interaction forces. The CoP and GRF variations are calculated from the difference between the estimated values (assuming no interaction forces) using a pre-identified statically equivalent serial chain (SESC) and the measured ones (with the effect of interaction forces) using an external device. The calculated variation vectors and the measured joint angles of the human body are then used for the estimation of the overloading joint torques in real-time. We evaluated the efficacy of the proposed method both in simulations and experiments, in various poses of the human and interaction force profiles.

Double loop control strategy with different time steps based on human characteristics.

This paper proposes a cooperative control strategy in consideration of the force sensitivity of human. The strategy consists of two loops: one is the intention estimation loop whose sampling time can be variable in order to investigate the effect of the sampling time; the other is the position control loop with fixed time step. A high sampling rate is not necessary for the intention estimation loop due to the bandwidth of the mechanoreceptors in humans. In addition, the force sensor implemented in the robot is sensitive to the noise induced from the sensor itself and tremor of the human. Multiple experiments were performed with the experimental protocol using various time steps of the intention estimation loop to find the suitable sampling times in physical human robot interaction. The task involves pull-and-push movement with a two-degree-of-freedom robot, and the norm of the interaction force was obtained for each experiment as the measure of the cooperative control performance.