Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we ...report atomic-resolution crystal structures of Ca(2+)- and Mg(2+)-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca(2+)-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca(2+)-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca(2+)-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca(2+) triggering, moves en bloc as Ca(2+) influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.
We propose a novel unified passivity-based adaptive backstepping control framework for “mixed” quadrotor-type unmanned aerial vehicles (UAVs), which consists of the translation dynamics with thrust ...force input λ∈ℜ and the attitude kinematics with the angular velocity input w∈ℜ3 evolving on SE(3). We also show how our proposed unified framework can be used for velocity field following, timed trajectory tracking and haptic interaction over the Internet, while also providing a complete stability (or collision avoidance) analysis. Experiments using a real quadrotor and lossy communication (for the teleoperation) are also performed to illustrate the theory.
•Novel passivity-based adaptive backstepping control of under-actuated quadrotors.•Demonstrated for the velocity field and trajectory tracking control of the quadrotors.•Applied for stable haptic teleoperation of the quadrotor over the Internet.
The transition from a carbon-centered economy to an era of renewable energy has led to global attention on hydrogen energy, ultimately leading to the development of fuel cells using hydrogen as a ...fuel. In response to global demand, overall fuel cell technology has grown remarkably over the past few years; yet, commercialization remains sluggish owing to cost. As the cathode of a proton exchange membrane fuel cell (PEMFC), which is the most commercialized fuel cell, is markedly dependent on platinum (Pt), anion exchange membrane fuel cells (AEMFCs), which can utilize non-precious materials as cathode catalysts, have emerged as a promising alternative. Earth-abundant metals are used as cathode catalysts, and metal-free materials are used to achieve comparable performance to Pt. Compared to the single-cell performance of Pt catalysts, a gap still exists; however, the applicability of non-noble metals has been extensively evaluated. If catalyst development is accompanied by efficient electrode structure design, a significant part of the cost problem can be overcome. AEMFCs have advantages in the ORR of cathodes compared to PEMFCs; however, the HOR kinetics are quite sluggish. Therefore, the design of HOR catalysts requires another approach, not only to enhance their intrinsic activity, but also consider the poisoning induced by the use of ionomers besides PEMFCs. Therefore, a strategy based on the HOR pathway is required to lower the barrier of the rate-determining step. In this review, catalysts for AEMFCs were introduced based on their classification, and information on recent trends and issues related to catalysts was presented.
Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this ...epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.
Mutations in the mitofusin 2 (MFN2) gene, which encodes a mitochondrial GTPase mitofusin protein, have recently been reported to cause both Charcot–Marie–Tooth 2A (CMT2A) and hereditary motor and ...sensory neuropathy VI (HMSN VI). It is well known that HMSN VI is an axonal CMT neuropathy with optic atrophy. However, the differences between CMT2A and HMSN VI with MFN2 mutations remained to be clarified. Therefore, we studied the phenotypic characteristics of CMT patients with MFN2 mutations. Mutations in MFN2 were screened in 62 unrelated axonal CMT neuropathy families. We calculated CMT neuropathy scores (CMTNSs) and functional disability scales (FDSs) to quantify disease severity. Twenty-one patients with the MFN2 mutations were studied by brain MRI. Ten pathogenic mutations were identified in 26 patients from 15 families (24.2%). Six of these mutations had not been reported, and de novo mutations were observed in five families (33.3%). The electrophysiological patterns of affected individuals with the MFN2 mutations were typical of axonal CMT; however, the clinical and electrophysiological characteristics were markedly different in early (<10 years) and late disease-onset (≥10 years) groups. All patients with an early onset had severe CMTNS (≥21) and FDS (6 or 7), whereas most patients with late onset had mild CMTNS (≤10) and FDS (≤3). We identified two HMSN VI families with the R364W mutation in the early onset group; however, two other families with the same mutation did not have optic atrophy. In addition, two early onset families with R94W mutations, previously reported for HMSN VI, did not have visual impairment. Interestingly, eight patients had periventricular and subcortical hyperintense lesions by brain MRI. In the late-onset group, three patients had sensorineural hearing loss and two had bilateral extensor plantar responses. We found that MFN2 mutations are the major cause of axonal CMT neuropathy, and that they are associated with variable CNS involvements. Phenotypes were significantly different in the early and late disease-onset groups. Our findings suggest that HMSN VI might be a variant of the early onset severe CMT2A phenotype.
Astrocytes are proposed to participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. However, the molecules involved in metabolic ...sensing and the molecular pathways responsible for metabolic coupling between different cell types in the brain are not fully understood. Here we show that a recently cloned bicarbonate (HCO3−) sensor, soluble adenylyl cyclase (sAC), is highly expressed in astrocytes and becomes activated in response to HCO3− entry via the electrogenic NaHCO3 cotransporter (NBC). Activated sAC increases intracellular cAMP levels, causing glycogen breakdown, enhanced glycolysis, and the release of lactate into the extracellular space, which is subsequently taken up by neurons for use as an energy substrate. This process is recruited over a broad physiological range of K+ext and also during aglycemic episodes, helping to maintain synaptic function. These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons.
► Astrocytes express bicarbonate-sensitive soluble adenylyl cyclase (sAC) ► Depolarization and bicarbonate entry increase cAMP in astrocytes ► sAC triggers glycogen breakdown and lactate efflux from astrocytes ► sAC protects synaptic function by lactate efflux from astrocytes
Choi et al. show that astrocytes express bicarbonate-sensitive soluble adenylyl cyclase that acts as a metabolic sensor of neuronal activity and supplies lactate derived from glycogen breakdown in astrocytes to maintain neuronal activity when alternative energy sources are needed.
Microglia, the brain's immune cells, maintain homeostasis and sense pathological changes by continuously surveying the parenchyma with highly motile large processes. Here, we demonstrate that ...microglia also use thin actin-dependent filopodia that allow fast nanoscale sensing within discrete regions. Filopodia are distinct from large processes by their size, speed, and regulation mechanism. Increasing cyclic AMP (cAMP) by activating norepinephrine G
-coupled receptors, applying nitric oxide, or inhibiting phosphodiesterases rapidly increases filopodia but collapses large processes. Alternatively, G
-coupled P2Y12 receptor activation collapses filopodia but triggers large processes extension with bulbous tips. Similar control of cytoskeletal dynamics and microglial morphology by cAMP is observed in ramified primary microglia, suggesting that filopodia are intrinsically generated sensing structures. Therefore, nanoscale surveillance of brain parenchyma by microglia requires localized cAMP increases that drive filopodia formation. Shifting intracellular cAMP levels controls the polarity of microglial responses to changes in brain homeostasis and alters the scale of immunosurveillance.
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