Binding mechanism and antagonism of the vesicular acetylcholine transporter VAChT.

The vesicular acetylcholine transporter (VAChT) has a pivotal role in packaging and transporting acetylcholine for exocytotic release, serving as a vital component of cholinergic neurotransmission. Dysregulation of its function can result in neurological disorders. It also serves as a target for developing radiotracers to quantify cholinergic neuron deficits in neurodegenerative conditions.

Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits.

The paraventricular hypothalamus (PVH) is crucial for food intake control, yet the presynaptic mechanisms underlying PVH neurons remain unclear. Here, we show that RUVBL2 in the PVH is significantly reduced during energy deficit, and knockout (KO) of PVH RUVBL2 results in hyperphagic obesity in mice. RUVBL2-expressing neurons in the PVH (PVH) exert the anorexigenic effect by projecting to the arcuate hypothalamus, the dorsomedial hypothalamus, and the parabrachial complex.

Synaptotagmin-11 Inhibits Synaptic Vesicle Endocytosis via Endophilin A1.

Synaptic vesicle (SV) endocytosis is a critical and well-regulated process for the maintenance of neurotransmission. We previously reported that synaptotagmin-11 (Syt11), an essential non-Ca-binding Syt associated with brain diseases, inhibits neuronal endocytosis (Wang et al., 2016).

Molecular insights into the gating mechanisms of voltage-gated calcium channel Ca2.3.

High-voltage-activated R-type Ca2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human Ca2.

MC4R Deficiency Causes Dysregulation of Postsynaptic Excitatory Synaptic Transmission as a Crucial Culprit for Obesity.

Melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVH) shows bidirectional characterization in modulating food intake and energy homeostasis. We demonstrate that MC4R knockdown (KD) in the PVH can attenuate AMPA receptor (AMPAR)-mediated postsynaptic responses by altering the phosphorylation of AMPAR GluA1 subunit through the protein kinase A (PKA)-dependent signaling cascade and simultaneously lead to rapid body weight gain. Furthermore, PKA KD in the PVH engendered similar electrophysiological and behavioral phenotypes as in MC4R KD mice.

Face image-sketch synthesis via generative adversarial fusion.

Face image-sketch synthesis is widely applied in law enforcement and digital entertainment fields. Despite the extensive progression in face image-sketch synthesis, there are few methods focusing on generating a color face image from a sketch. The existing methods pay less attention to learning the illumination or highlight distribution on the face region.

Structural basis for modulation of human Na1.3 by clinical drug and selective antagonist.

Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception.

Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells.

The intestinal microbiota closely interacts with the neuroendocrine system and exerts profound effects on host physiology. Here, we report that nucleotide-binding oligomerization domain 1 (Nod1) ligand derived from intestinal bacteria modulates catecholamine storage and secretion in mouse adrenal chromaffin cells. The cytosolic peptidoglycan receptor Nod1 is involved in chromogranin A (Chga) retention in dense core granules (DCGs) in chromaffin cells.

Measurement of intact quantal packet of transmitters released from single nerve terminal by loose-patch amperometry.

Neuronal information is majorly encoded chemically at synapses and the elementary unit of synaptic transmission is the contents of neurotransmitter released from single vesicle. However, the contents of quantal neurotransmitter have never been precisely estimated at synapses, which largely prevent our understanding the nature of quantal neurotransmitter release and its impact on neuronal information processing. In order to break through the technical bottleneck of precisely counting quantal neurotransmitter molecules, we developed a new approach in combination of electrophysiology and electrochemistry to measure intact quantal content of single vesicles.

A comprehensive study on the combustion kinetic modeling of typical electronic plastic waste-television set (TV) plastic shell.

Electronic waste is the fastest growing waste stream and one of the most significant constituents is electronic plastics. In this study, the combustion kinetic of typical electronic plastic waste-television set (TV) plastic shell-was investigated using two basic kinetic methods. The reaction mechanism and kinetic compensation effect were probed as well.

Synapse and Active Zone Assembly in the Absence of Presynaptic Ca Channels and Ca Entry.

Presynaptic Ca2 channels are essential for Ca-triggered exocytosis. In addition, there are two competing models for their roles in synapse structure. First, Ca channels or Ca entry may control synapse assembly.

Random Shapley Forests: Cooperative Game-Based Random Forests With Consistency.

The original random forests (RFs) algorithm has been widely used and has achieved excellent performance for the classification and regression tasks. However, the research on the theory of RFs lags far behind its applications. In this article, to narrow the gap between the applications and the theory of RFs, we propose a new RFs algorithm, called random Shapley forests (RSFs), based on the Shapley value.

Banzhaf random forests: Cooperative game theory based random forests with consistency.

Random forests algorithms have been widely used in many classification and regression applications. However, the theory of random forests lags far behind their applications. In this paper, we propose a novel random forests classification algorithm based on cooperative game theory.

Sr has low efficiency in regulating spontaneous release at the Calyx of Held synapses.

It has been known that Ca plays an essential role in mediating different modes of neurotransmitter release via different sensing mechanisms. Synaptotagmin 1, 2, and 9 were found to act as the Ca sensors for synchronous release and synaptotagmin 7 and Doc-2 were proposed as the Ca sensors for asynchronous release. Comparatively, the Ca sensor for spontaneous release remains a mystery.

Ion- and water-binding sites inside an occluded hourglass pore of a trimeric intracellular cation (TRIC) channel.

Background: Trimeric intracellular cation (TRIC) channels are crucial for Ca handling in eukaryotes and are involved in K uptake in prokaryotes. Recent studies on the representative members of eukaryotic and prokaryotic TRIC channels demonstrated that they form homotrimeric units with the ion-conducting pores contained within each individual monomer.

Results: Here we report detailed insights into the ion- and water-binding sites inside the pore of a TRIC channel from Sulfolobus solfataricus (SsTRIC).

Spontaneous Vesicle Release Is Not Tightly Coupled to Voltage-Gated Calcium Channel-Mediated Ca2+ Influx and Is Triggered by a Ca2+ Sensor Other Than Synaptotagmin-2 at the Juvenile Mice Calyx of Held Synapses.

It is well known that voltage-gated calcium channels (VGCCs)-mediated Ca(2+) influx triggers evoked synaptic vesicle release. However, the mechanisms of Ca(2+) regulation of spontaneous miniature vesicle release (mini) remain poorly understood. Here we show that blocking VGCCs at the juvenile mice (C57BL/6) calyx of Held synapse failed to cause an immediate change in minis.

Quantitative analysis of vesicle recycling at the calyx of Held synapse.

Vesicle recycling is pivotal for maintaining reliable synaptic signaling, but its basic properties remain poorly understood. Here, we developed an approach to quantitatively analyze the kinetics of vesicle recycling with exquisite signal and temporal resolution at the calyx of Held synapse. The combination of this electrophysiological approach with electron microscopy revealed that ∼80% of vesicles (∼270,000 out of ∼330,000) in the nerve terminal are involved in recycling.

Microsecond dissection of neurotransmitter release: SNARE-complex assembly dictates speed and Ca²⁺ sensitivity.

SNARE-complex assembly mediates synaptic vesicle fusion during neurotransmitter release and requires that the target-SNARE protein syntaxin-1 switches from a closed to an open conformation. Although many SNARE proteins are available per vesicle, only one to three SNARE complexes are minimally needed for a fusion reaction. Here, we use high-resolution measurements of synaptic transmission in the calyx-of-Held synapse from mutant mice in which syntaxin-1 is rendered constitutively open and SNARE-complex assembly is enhanced to examine the relation between SNARE-complex assembly and neurotransmitter release.

Emotional regulation of pain: the role of noradrenaline in the amygdala.

The perception of pain involves the activation of the spinal pathway as well as the supra-spinal pathway, which targets brain regions involved in affective and cognitive processes. Pain and emotions have the capacity to influence each other reciprocally; negative emotions, such as depression and anxiety, increase the risk for chronic pain, which may lead to anxiety and depression. The amygdala is a key-player in the expression of emotions, receives direct nociceptive information from the parabrachial nucleus, and is densely innervated by noradrenergic brain centers.

Bulk endocytosis at neuronal synapses.

Neurotransmitter-containing synaptic vesicle (SV) fusion with the nerve terminal plasma membrane initiates neurotransmission in response to neuronal excitation. Under mild stimulation, the fused vesicular membrane is retrieved via kiss-and-run and/or clathrin-mediated endocytosis, which is sufficient to maintain recycling of SVs. When neurons are challenged with very high stimulation, the number of fused SVs can be extremely high, resulting in significant plasma membrane addition.

Building a better dynasore: the dyngo compounds potently inhibit dynamin and endocytosis.

Dynamin GTPase activity increases when it oligomerizes either into helices in the presence of lipid templates or into rings in the presence of SH3 domain proteins. Dynasore is a dynamin inhibitor of moderate potency (IC₅₀ ~ 15 μM in vitro). We show that dynasore binds stoichiometrically to detergents used for in vitro drug screening, drastically reducing its potency (IC₅₀ = 479 μM) and research tool utility.

A dual-Ca2+-sensor model for neurotransmitter release in a central synapse.

Ca2+-triggered synchronous neurotransmitter release is well described, but asynchronous release-in fact, its very existence-remains enigmatic. Here we report a quantitative description of asynchronous neurotransmitter release in calyx-of-Held synapses. We show that deletion of synaptotagmin 2 (Syt2) in mice selectively abolishes synchronous release, allowing us to study pure asynchronous release in isolation.

Dual modes of Munc18-1/SNARE interactions are coupled by functionally critical binding to syntaxin-1 N terminus.

The SM (Sec1/Munc18-like) protein Munc18-1 and the soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) proteins syntaxin-1, SNAP-25, and synaptobrevin/VAMP (vesicle-associated membrane protein) constitute the core fusion machinery for synaptic vesicle exocytosis. Strikingly, Munc18-1 interacts with neuronal SNARE proteins in two distinct modes (i.e.