微細CMOSデバイスの信頼性モデリングの研究

修士論

Fast cerebellar reflex circuitry requires synaptic vesicle priming by Munc13-3

Munc13-3 is a member of the Munc13 family of synaptic vesicle priming proteins and mainly expressed in cerebellar neurons. Munc13-3 null mutant (Munc13-3(−/−)) mice show decreased synaptic release probability at parallel fiber to Purkinje cell, granule cell to Golgi cell, and granule cell to basket cell synapses and exhibit a motor learning deficit at highest rotarod speeds. Since we detected Munc13-3 immunoreactivity in the dentate gyrus, as reported here for the first time, and current studies indicated a crucial role for the cerebellum in hippocampus-dependent spatial memory, we systematically investigated Munc13-3(−/−) mice versus wild-type littermates of both genders with respect to hippocampus-related cognition and a range of basic behaviors, including tests for anxiety, sensory functions, motor performance and balance, sensorimotor gating, social interaction and competence, and repetitive and compulsive behaviors. Neither basic behavior nor hippocampus-dependent cognitive performance, evaluated by Morris water maze, hole board working and reference memory, IntelliCage-based place learning including multiple reversals, and fear conditioning, showed any difference between genotypes. However, consistent with a disturbed cerebellar reflex circuitry, a reliable reduction in the acoustic startle response in both male and female Munc13-3(−/−) mice was found. To conclude, complete deletion of Munc13-3 leads to a robust decrease in the acoustic startle response. This readout of a fast cerebellar reflex circuitry obviously requires synaptic vesicle priming by Munc13-3 for full functionality, in contrast to other behavioral or cognitive features, where a nearly perfect compensation of Munc13-3 deficiency by related synaptic proteins has to be assumed

Munc13-1 is a Ca2+-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission

During ongoing presynaptic action potential (AP) firing, transmitter release is limited by the availability of release-ready synaptic vesicles (SVs). The rate of SV recruitment (SVR) to release sites is strongly upregu- lated at high AP frequencies to balance SV consumption. We show that Munc13-1—an essential SV priming protein—regulates SVR via a Ca2+-phospholipid-dependent mechanism. Using knockin mouse lines with point mutations in the Ca2+-phospholipid-binding C2B domain of Munc13-1, we demonstrate that abolishing Ca2+-phospholipid binding increases synaptic depression, slows recovery of synaptic strength after SV pool depletion, and reduces temporal fidelity of synaptic transmission, while increased Ca2+-phospholipid binding has the opposite effects. Thus, Ca2+-phospholipid binding to the Munc13-1-C2B domain accelerates SVR, reduces short-term synaptic depression, and increases the endurance and temporal fidelity of neurotrans- mission, demonstrating that Munc13-1 is a core vesicle priming hub that adjusts SV re-supply to demand

Cumulative fatigue damage of stress below the fatigue limit in weldment steel under block loading

To investigate the cumulative fatigue damage below the fatigue limit of multipass weldment martensitic stainless steel, and to clarify the effect of cycle ratios and high‐stress level in the statement, fatigue tests were conducted under constant and combined high‐ and low‐stress amplitude relative to stress above and below the fatigue limit. The outcomes indicate that neither modified Miner's nor Haibach's approach provided accurate evaluation under repeated two‐step amplitude loading. Moreover, effect of cycle ratios has been determined. Additionally, the cumulative fatigue damage saturated model is established and validated. Cumulative fatigue damage contributed by low‐stress below the fatigue limit in high stress of 700 MPa is higher than that with 650 MPa at identical conditions (fatigue limit 575 MPa). Thus, high stress affects fatigue damage behaviour below the fatigue limit. A new predicted approach has been proposed based on Corten‐Dolan law, whose accuracy and applicability have been proven

Who would be affected by a ban on disposable vapes? A population study in Great Britain

OBJECTIVE: The UK government is consulting on banning disposable e-cigarettes. This study aimed to describe trends in disposable e-cigarette use among adults in Great Britain since 2021 and establish who would currently be affected by a ban on disposables. STUDY DESIGN: Nationally-representative monthly cross-sectional survey. METHODS: We analysed data from 69,973 adults surveyed between January 2021 and August 2023. We estimated monthly time trends in the weighted prevalence of current disposable e-cigarette use among adults and by sociodemographic characteristics and smoking status. RESULTS: From January 2021 to August 2023, the prevalence of disposable e-cigarette use grew from 0.1 % to 4.9 %. This rise was observed across all population subgroups but was most pronounced among younger adults (e.g. reaching 15.9 % of 18-year-olds compared with 1.3 % of 65-year-olds), those who currently smoke (16.3 %), and those who stopped smoking in the past year (18.2 %). Use among never smokers remained relatively rare (1.5 %), except among 18- to 24-year-olds (7.1 %). Use was significantly higher in England than Wales or Scotland (5.3 % vs. 2.0 % and 2.8 %) and among less (vs. more) advantaged social grades (6.1 % vs. 4.0 %), those with (vs. without) children (6.4 % vs. 4.4 %), and those with (vs. without) a history of mental health conditions (9.3 % vs. 3.1 %). CONCLUSIONS: A ban on disposable e-cigarettes would currently affect one in 20 adults in Great Britain (approximately 2.6 million people). The proportion who would be affected would be greatest among young people, including the 316,000 18-24 year-olds who currently use disposables but who have never regularly smoked tobacco, which may discourage uptake of vaping in this group. However, a ban would also affect 1.2 million people who currently smoke and a further 744,000 who previously smoked. It would also have a disproportionate impact on disadvantaged groups that have higher rates of smoking and typically find it harder to quit

Regulation of releasable vesicle pool sizes by protein kinase A-dependent phosphorylation of SNAP-25

AbstractProtein kinase A (PKA) is a key regulator of neurosecretion, but the molecular targets remain elusive. We combined pharmacological manipulations of kinase and phosphatase activities with mutational studies on the exocytotic machinery driving fusion of catecholamine-containing vesicles from chromaffin cells. We found that constitutive PKA activity was necessary to maintain a large number of vesicles in the release-ready, so-called primed, state, whereas calcineurin (protein phosphatase 2B) activity antagonized this effect. Overexpression of the SNARE protein SNAP-25a mutated in a PKA phosphorylation site (Thr-138) eliminated the effect of PKA inhibitors on the vesicle priming process. Another, unidentified, PKA target regulated the relative size of two different primed vesicle pools that are distinguished by their release kinetics. Overexpression of the SNAP-25b isoform increased the size of both primed vesicle pools by a factor of two, and mutations in the conserved Thr-138 site had similar effects as in the a isoform

Photoswitchable diacylglycerols enable optical control of protein kinase C.

Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling

BACE1 inhibition more effectively suppresses initiationthan progression of β-amyloid pathology

International audienc

Heated tobacco products for smoking cessation and reducing smoking prevalence

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effectiveness and safety of HTPs for smoking cessation and the impact of HTPs on smoking prevalence